TY - JOUR AB - STAT3-hyper-IgE syndrome (STAT3-HIES) is an inborn error of immunity caused by heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). In this study, we evaluate the functional relevance of a previously undescribed heterozygous STAT3 variant in a patient with clinical findings of STAT3-HIES. Flow cytometry, quantitative real-time PCR, pull-down assays, native PAGE, DNA-binding ELISA, and 3D-structural data analysis were performed. Genetic analysis identified the heterozygous STAT3 variant NM_139276.2:c.2127G>C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3-HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild-type STAT3 in STAT3-deficient cells indicated a dominant-negative effect by the mutation. Analysis of 3D-structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C-terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3-HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation. AU - Hagl, B. AU - Spielberger, B.D.* AU - Neumann, B.* AU - Pelham, S.J.* AU - Pandey, D.* AU - Schlundt, A.* AU - Barro, C.* AU - Lechner, A.* AU - Wolf, C.* AU - Deenick, E.K.* AU - Sattler, M. AU - Tangye, S.G.* AU - Rothenfusser, S.* AU - Renner, E.D.* C1 - 75296 C2 - 57928 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Signal transducer and activator of transcription 3 (STAT3) variant p.K709N causes hyper-IgE syndrome likely by impaired STAT3-dimer formation. JO - Eur. J. Immunol. VL - 55 IS - 7 PB - Wiley PY - 2025 SN - 0014-2980 ER - TY - JOUR AB - Signaling pathways involving NF-κB transcription factors have essential roles in inflammation, immunity, cell proliferation, differentiation, and survival. Classical IκB proteins, such as IκBα and IκBβ, bind to NF-κB via ankyrin repeats to sequester NF-κB in the cytoplasm and thus suppress NF-κB activity. Unlike these constitutively expressed classical IκBs, the expression of the atypical IκBs Bcl-3, IκBNS, and IκBζ is induced in immune cells after recognition of antigens, pathogen-associated molecular patterns (PAMPs) or cytokines, upon which they localize to the nucleus and form complexes with transcription factors and regulators on the DNA. Atypical, nuclear IκBs have been proposed to modulate NF-κB activity in a context-dependent manner as they can either inhibit or increase gene expression of a subset of NF-κB target genes. This complexity may be related to the molecular function of atypical IκBs, which bind to different transcription factor complexes and form a bridge to different cofactors or epigenetic modifiers. Recent research has identified novel target genes of atypical IκBs that include chemokines, cytokines, and master regulators of lymphocyte differentiation, underscoring prominent roles in adaptive immune and autoimmune responses. Here, we summarize our current understanding of atypical IκBs in lymphocytes with a focus on their emerging role in autoimmunity. AU - Kübelbeck, T.* AU - Wichmann, N. AU - Raj, T.* AU - Raj, C.* AU - Ohnmacht, C. AU - Hövelmeyer, N.* AU - Kramer, D.* AU - Heissmeyer, V. C1 - 74552 C2 - 57510 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Regulation and function of the atypical IκBs-Bcl-3, IκBNS, and IκBζ-in lymphocytes and autoimmunity. JO - Eur. J. Immunol. VL - 55 IS - 5 PB - Wiley PY - 2025 SN - 0014-2980 ER - TY - JOUR AU - Masanetz, R.K.* AU - Meiser, P.* AU - Wahida, A. AU - Afzali, A.M.* AU - Akl, C.F.* AU - Esser-von Bieren, J. AU - Boztug, K.* AU - Ullrich, E.* C1 - 75472 C2 - 58019 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - 2025 German society for immunology prizes. JO - Eur. J. Immunol. VL - 55 IS - 9 PB - Wiley PY - 2025 SN - 0014-2980 ER - TY - JOUR AB - Cytotoxicity is a cornerstone of immune defense, critical for combating tumors and infections. This process relies on the coordinated action of granzymes and pore-forming proteins, with granzyme B (GZMB) and perforin (PRF1) being key markers and the most widely studied molecules pertaining to cytotoxicity. However, other human granzymes and cytotoxic components remain underexplored, despite growing evidence of their distinct, context-dependent roles. Natural killer cell granule protein 7 (NKG7) has recently emerged as a crucial cytotoxicity regulator, yet its expression patterns and function are poorly understood. Using large publicly available single-cell RNA sequencing atlases, we performed a comprehensive profiling of cytotoxicity across immune subsets and tissues. Our analysis highlights NKG7 expression as a strong marker of cytotoxicity, exhibiting a strong correlation with overall cytotoxic activity (r = 0.97) and surpassing traditional markers such as granzyme B and perforin in reliability. Furthermore, NKG7 expression is notably consistent across diverse immune subsets and tissues, reinforcing its versatility and robustness as a cytotoxicity marker. These findings position NKG7 as an invaluable tool for evaluating immune responses and a reliable indicator of cytotoxic functionality across biological and clinical contexts. AU - Turiello, R.* AU - Ng, S.S.* AU - Tan, E.* AU - van der Voort, G.* AU - Salim, N.* AU - Yong, M.C.R.* AU - Khassenova, M.* AU - Oldenburg, J.* AU - Rühl, H.* AU - Hasenauer, J. AU - Surace, L.* AU - Toma, M.* AU - Bald, T.* AU - Hölzel, M.* AU - Corvino, D.* C1 - 74988 C2 - 57778 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - NKG7 is a stable marker of cytotoxicity across immune contexts and within the tumor microenvironment. JO - Eur. J. Immunol. VL - 55 IS - 6 PB - Wiley PY - 2025 SN - 0014-2980 ER - TY - JOUR AB - A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-κB and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-κB and JNK. Utilizing a novel set of A20 mutants in NF-κB and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-κB and JNK signaling. AU - Dabbah-Krancher, G.* AU - Ruchinskas, A.* AU - Kallarakal, M.A.* AU - Lee, K.P.* AU - Bauman, B.M.* AU - Epstein, B.* AU - Yin, H. AU - Krappmann, D. AU - Schaefer, B.C.* AU - Snow, A.L.* C1 - 71889 C2 - 56472 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling. JO - Eur. J. Immunol. PB - Wiley PY - 2024 SN - 0014-2980 ER - TY - JOUR AB - Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID-19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS-CoV-2 infected outpatients with mild disease and compared it to the response of healthy individuals to yellow fever vaccine virus YF17D as a model of a well-coordinated response to viral infection. In SARS-CoV-2-infected outpatients circulating DCs were persistently reduced for several weeks whereas after YF17D vaccination DC numbers were decreased temporarily and rapidly replenished by increased proliferation until 14 days after vaccination. The majority of COVID-19 outpatients showed high expression of CD86 and PD-L1 in monocytes and DCs early on, resembling the dynamic after YF17D vaccination. In a subgroup of patients low CD86 and high PD-L1 expression were detected in monocytes and DCs coinciding with symptoms, higher age and lower lymphocyte counts. This phenotype was similar to that observed in severely ill COVID-19 patients, but less pronounced. Thus, prolonged reduction and dysregulated activation of blood DCs and monocytes were seen in a subgroup of symptomatic non-hospitalized COVID-19 patients while a transient coordinated activation was characteristic for the majority of patients with mild COVID-19 and the response to YF17D vaccination. This article is protected by copyright. All rights reserved. AU - Winheim, E.* AU - Eser, T.* AU - Deák, F.* AU - Ahmed, M.I.M.* AU - Baranov, O.* AU - Rinke, L.* AU - Eisenächer, K.* AU - Santos-Peral, A. AU - Karimzadeh, H. AU - Pritsch, M. AU - Scherer, C.* AU - Muenchhoff, M.* AU - Hellmuth, J.C.* AU - von Bergwelt-Baildon, M.* AU - Olbrich, L.* AU - Hoelscher, M.* AU - Wieser, A.* AU - Kroidl, I.* AU - Rothenfußer, S. AU - Geldmacher, C.* AU - Krug, A.B.* C1 - 66868 C2 - 53336 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Distinct and dynamic activation profiles of circulating dendritic cells and monocytes in mild COVID-19 and after yellow fever vaccination. JO - Eur. J. Immunol. VL - 53 IS - 3 PB - Wiley PY - 2022 SN - 0014-2980 ER - TY - JOUR AB - Pyroptosis is a type of acute cell death that mainly occurs in immune cells. It is characterized with robust release of inflammatory cytokines and has emerged to play a critical role in the pathogenesis of sepsis-associated immune disorders. In this study, we screened for pyroptotic inhibitors with the ultimate goal to benefit sepsis treatments. Accidentally, we identified nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, blocking non-canonical pyroptosis. Using murine immortalized bone-marrow derived macrophage and human THP-1 cell line, we further discovered that NTS not only inhibits non-canonical pyroptosis mediated by caspase-11 or caspase-4, but also canonical pyroptosis mediated by caspase-1. Mechanistically, NTS directly inhibits the enzyme activities of these inflammatory caspases, and these inhibitory effects persist despite extensive washout of the drug. By contrast, apoptosis mediated by caspase-3/-7 was not affected by NTS. Mice pretreated with NTS intraperitoneally displayed improved survival rate and extended survival time in LPS- and polymicrobe-induced septic models respectively. In conclusion, NTS is a selective inhibitor of inflammatory caspases which blocks both the non-canonical and canonical pyroptotic pathways. It is safe for intraperitoneal administration and might be used as a prototype to develop drugs for sepsis treatments. AU - Chen, Q.* AU - Zheng, J. AU - Wang, D.* AU - Liu, Q.* AU - Kang, L.* AU - Gao, X.* AU - Lin, Z.* C1 - 61095 C2 - 50043 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1234-1245 TI - Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock. JO - Eur. J. Immunol. VL - 51 IS - 5 PB - Wiley PY - 2021 SN - 0014-2980 ER - TY - JOUR AB - The prevalence of asthma and other allergic diseases has rapidly increased in 'Westernized' countries over recent decades. This rapid increase suggests the involvement of environmental factors, behavioral changes or lifestyle, rather than genetic drift. It has become increasingly clear that the microbiome plays a key role in educating the host immune system and thus regulation of disease susceptibility. This review will focus on recent advances uncovering immunological and microbial mechanisms that protect against allergies, in particular within the context of a farming environment. A whole body of epidemiological data disclosed the nature of the protective exposures in a farm. Current evidence points towards an important role of the host microbiome in setting an immunological equilibrium that determines progression towards, or protection against allergic diseases. Conclusive mechanistic insights on how microbial exposures prevent from developing allergic diseases in humans is still lacking but findings from experimental models reveal plausible immunological mechanisms. Gathering further knowledge on these mechanisms and confirming their relevance in humans is of great importance in order to develop preventive strategies for children at risk of developing allergies. AU - Deckers, J.* AU - Marsland, B.J.* AU - von Mutius, E. C1 - 62890 C2 - 51144 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Protection against allergies: Microbes, immunity and the farming effect. JO - Eur. J. Immunol. PB - Wiley PY - 2021 SN - 0014-2980 ER - TY - JOUR AU - Monti, P.* AU - Vignali, D.* AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 58865 C2 - 48412 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 903-905 TI - Soluble IL-7 receptor alpha concentration in cord blood is linked to sex and maternal diabetes, but not with subsequent development of type 1 diabetes. JO - Eur. J. Immunol. VL - 50 IS - 6 PB - Wiley PY - 2020 SN - 0014-2980 ER - TY - JOUR AU - Alhasan, M.* AU - Cait, A.* AU - Heimesaat, M.M.* AU - Blaut, M.* AU - Klopfleisch, R.* AU - Yildirim, A.Ö. AU - Sodemann, E.B.* AU - Bereswill, S.* AU - Conrad, M.L.* C1 - 57280 C2 - 47652 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1594-1595 TI - Antibiotic use during pregnancy impacts neonatal microbiota composition and increases offspring asthma severity. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Behrens, G. AU - Nina, K. AU - Csaba, G.* AU - Raj, T.* AU - Monecke, T.* AU - Zimmer, R.* AU - Niessing, D. AU - Heissmeyer, V. C1 - 57053 C2 - 47484 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 221-222 TI - Roquin and Regnase-1 cooperatively determine cell fate decisions in T cells. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AB - The interdependence of posttranscriptional gene regulation via miRNA and transcriptional regulatory networks in lymphocyte development is poorly understood. Here, we identified miR-191 as direct upstream modulator of a transcriptional module comprising the transcription factors Foxp1, E2A, and Egr1. Deletion as well as ectopic expression of miR-191 resulted in developmental arrest in B lineage cells, indicating that fine tuning of the combined expression levels of Foxp1, E2A, and Egr1, which in turn control somatic recombination and cytokine-driven expansion, constitutes a prerequisite for efficient B-cell development. In conclusion, we propose that miR-191 acts as a rheostat in B-cell development by fine tuning a key transcriptional program. AU - Blume, J.* AU - Ziętara, N.* AU - Witzlau, K.* AU - Liu, Y.* AU - Ortiz, O. AU - Puchałka, J.* AU - Winter, S.J.* AU - Kunze-Schumacher, H.* AU - Saran, N.* AU - Düber, S.* AU - Roy, B.* AU - Weiss, S.* AU - Klein, C.* AU - Wurst, W. AU - Łyszkiewicz, M.* AU - Krueger, A.* C1 - 54448 C2 - 45594 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 121-132 TI - miR-191 modulates B-cell development and targets transcription factors E2A, Foxp1, and Egr1. JO - Eur. J. Immunol. VL - 49 IS - 1 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AB - These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion. AU - Cossarizza, A.* AU - Chang, H.D.* AU - Radbruch, A.* AU - Acs, A.* AU - Adam, D.* AU - Adam-Klages, S.* AU - Agace, W.W.* AU - Aghaeepour, N.* AU - Akdis, M.* AU - Allez, M.* AU - Almeida, L.N.* AU - Alvisi, G.* AU - Anderson, G.* AU - Andrä, I.* AU - Annunziato, F.* AU - Anselmo, A.* AU - Bacher, P.* AU - Baldari, C.T.* AU - Bari, S.* AU - Barnaba, V.* AU - Barros-Martins, J.* AU - Battistini, L.* AU - Bauer, W.* AU - Baumgart, S.* AU - Baumgarth, N.* AU - Baumjohann, D.* AU - Baying, B.* AU - Bebawy, M.* AU - Becher, B.* AU - Beisker, W. AU - Benes, V.* AU - Beyaert, R.* AU - Blanco, A.* AU - Boardman, D.A.* AU - Bogdan, C.* AU - Borger, J.G.* AU - Borsellino, G.* AU - Boulais, P.E.* AU - Bradford, J.A.* AU - Brenner, D.* AU - Brinkman, R.R.* AU - Brooks, A.E.S.* AU - Busch, D.H.* AU - Büscher, M.* AU - Bushnell, T.P.* AU - Calzetti, F.* AU - Cameron, G.* AU - Cammarata, I.* AU - Cao, X.* AU - Cardell, S.L.* AU - Casola, S.* AU - Cassatella, M.A.* AU - Cavani, A.* AU - Celada, A.* AU - Chatenoud, L.* AU - Chattopadhyay, P.K.* AU - Chow, S.* AU - Christakou, E.* AU - Čičin-Šain, L.* AU - Clerici, M.* AU - Colombo, F.S.* AU - Cook, L.* AU - Cooke, A.* AU - Cooper, A.M.* AU - Corbett, A.J.* AU - Cosma, A.* AU - Cosmi, L.* AU - Coulie, P.G.* AU - Cumano, A.* AU - Cvetkovic, L.* AU - Dang, V.D.* AU - Dang-Heine, C.* AU - Davey, M.S.* AU - Davies, D.* AU - De Biasi, S.* AU - Del Zotto, G.* AU - Dela Cruz, G.V.* AU - Delacher, M.* AU - Della Bella, S.* AU - Dellabona, P.* AU - Deniz, G.* AU - Dessing, M.* AU - Di Santo, J.P.* AU - Diefenbach, A.* AU - Dieli, F.* AU - Dolf, A.* AU - Dörner, T.* AU - Dress, R.J.* AU - Dudziak, D.* AU - Dustin, M.* AU - Dutertre, C.A.* AU - Ebner, F.* AU - Eckle, S.B.G.* AU - Edinger, M.* AU - Eede, P.* AU - Ehrhardt, G.R.A.* AU - Eich, M.* AU - Engel, P.* AU - Engelhardt, B.* AU - Erdei, A.* AU - Esser, C.* AU - Everts, B.* AU - Evrard, M.* AU - Falk, C.S.* AU - Fehniger, T.A.* AU - Felipo-Benavent, M.* AU - Ferry, H.* AU - Feuerer, M.* AU - Filby, A.* AU - Filkor, K.* AU - Fillatreau, S.* AU - Follo, M.* AU - Förster, I.* AU - Foster, J.* AU - Foulds, G.A.* AU - Frehse, B.* AU - Frenette, P.S.* AU - Frischbutter, S.* AU - Fritzsche, W.* AU - Galbraith, D.W.* AU - Gangaev, A.* AU - Garbi, N.* AU - Gaudilliere, B.* AU - Gazzinelli, R.T.* AU - Geginat, J.* AU - Gerner, W.* AU - Gherardin, N.A.* AU - Ghoreschi, K.* AU - Gibellini, L.* AU - Ginhoux, F.* AU - Goda, K.* AU - Godfrey, D.I.* AU - Goettlinger, C.* AU - González-Navajas, J.M.* AU - Goodyear, C.S.* AU - Gori, A.* AU - Grogan, J.L.* AU - Grummitt, D.* AU - Grützkau, A.* AU - Haftmann, C.* AU - Hahn, J.* AU - Hammad, H.* AU - Hämmerling, G.* AU - Hansmann, L.* AU - Hansson, G.K.* AU - Harpur, C.M.* AU - Hartmann, S.* AU - Hauser, A.* AU - Hauser, A.E.* AU - Haviland, D.L.* AU - Hedley, D.* AU - Hernández, D.C.* AU - Herrera, G.* AU - Hermann, M.* AU - Hess, C.* AU - Höfer, T.* AU - Hoffmann, P.* AU - Hogquist, K.* AU - Holland, T.* AU - Höllt, T.* AU - Holmdahl, R.* AU - Hombrink, P.* AU - Houston, J.P.* AU - Hoyer, B.F.* AU - Huang, B.* AU - Huang, F.P.* AU - Huber, J.E.* AU - Huehn, J.* AU - Hundemer, M.* AU - Hunter, C.A.* AU - Hwang, W.Y.K.* AU - Iannone, A.G.* AU - Ingelfinger, F.* AU - Ivison, S.M.* AU - Jäck, H.M.* AU - Jani, P.K.* AU - Jávega, B.* AU - Jonjic, S.* AU - Kaiser, T.* AU - Kalina, T.* AU - Kamradt, T.* AU - Kaufmann, S.H.E.* AU - Keller, B.* AU - Ketelaars, S.L.C.* AU - Khalilnezhad, A.* AU - Khan, S.* AU - Kisielow, J.* AU - Klenerman, P.* AU - Knopf, J.* AU - Koay, H.F.* AU - Kobow, K.* AU - Kolls, J.K.* AU - Kong, W.T.* AU - Kopf, M.* AU - Korn, T.* AU - Kriegsmann, K.* AU - Kristyanto, H.* AU - Kroneis, T.* AU - Krueger, A.* AU - Kühne, J.* AU - Kukat, C.* AU - Kunkel, D.* AU - Kunze-Schumacher, H.* AU - Kurosaki, T.* AU - Kurts, C.* AU - Kvistborg, P.* AU - Kwok, I.* AU - Landry, J.* AU - Lantz, O.* AU - Lanuti, P.* AU - LaRosa, F.* AU - Lehuen, A.* AU - LeibundGut-Landmann, S.* AU - Leipold, M.D.* AU - Leung, L.Y.T.* AU - Levings, M.K.* AU - Lino, A.C.* AU - Liotta, F.* AU - Litwin, V.* AU - Liu, Y.* AU - Ljunggren, H.G.* AU - Lohoff, M.* AU - Lombardi, G.* AU - Lopez, L.* AU - López-Botet, M.* AU - Lovett-Racke, A.E.* AU - Lubberts, E.* AU - Luche, H.* AU - Ludewig, B.* AU - Lugli, E.* AU - Lunemann, S.* AU - Maecker, H.T.* AU - Maggi, L.* AU - Maguire, O.* AU - Mair, F.* AU - Mair, K.H.* AU - Mantovani, A.* AU - Manz, R.A.* AU - Marshall, A.J.* AU - Martínez-Romero, A.* AU - Martrus, G.* AU - Marventano, I.* AU - Maslinski, W.* AU - Matarese, G.* AU - Mattioli, A.V.* AU - Maueröder, C.* AU - Mazzoni, A.* AU - McCluskey, J.* AU - McGrath, M.* AU - McGuire, H.M.* AU - McInnes, I.B.* AU - Mei, H.E.* AU - Melchers, F.* AU - Melzer, S.* AU - Mielenz, D.* AU - Miller, S.D.* AU - Mills, K.H.G.* AU - Minderman, H.* AU - Mjösberg, J.* AU - Moore, J.* AU - Moran, B.* AU - Moretta, L.* AU - Mosmann, T.R.* AU - Müller, S.* AU - Multhoff, G. AU - Muñoz, L.E.* AU - Münz, C.* AU - Nakayama, T.* AU - Nasi, M.* AU - Neumann, K.* AU - Niedobitek, A.* AU - Nourshargh, S.* AU - Núñez, G.* AU - O'Connor, J.E.* AU - Ochel, A.* AU - Oja, A.* AU - Ordonez, D.* AU - Orfao, A.* AU - Orlowski-Oliver, E.* AU - Ouyang, W.* AU - Oxenius, A.* AU - Palankar, R.* AU - Panse, I.* AU - Pattanapanyasat, K.* AU - Paulsen, M.* AU - Pavlinic, D.* AU - Penter, L.* AU - Peterson, P.* AU - Peth, C.* AU - Petriz, J.* AU - Piancone, F.* AU - Pickl, W.F.* AU - Piconese, S.* AU - Pinti, M.* AU - Pockley, A.G.* AU - Podolska, M.J.* AU - Poon, Z.* AU - Pracht, K.* AU - Prinz, I.* AU - Pucillo, C.E.M.* AU - Quataert, S.A.* AU - Quatrini, L.* AU - Quinn, K.M.* AU - Radbruch, H.* AU - Radstake, T.R.D.J.* AU - Rahmig, S.* AU - Rahn, H.P.* AU - Rajwa, B.* AU - Ravichandran, G.* AU - Raz, Y.* AU - Rebhahn, J.A.* AU - Recktenwald, D.* AU - Reimer, D.* AU - Reis E Sousa, C.* AU - Remmerswaal, E.B.M.* AU - Richter, L.* AU - Rico, L.G.* AU - Riddell, A.* AU - Rieger, A.M.* AU - Robinson, J.P.* AU - Romagnani, C.* AU - Rubartelli, A.* AU - Ruland, J.* AU - Saalmüller, A.* AU - Saeys, Y.* AU - Saito, T.* AU - Sakaguchi, S.* AU - Sala-de-Oyanguren, F.* AU - Samstag, Y.* AU - Sanderson, S.* AU - Sandrock, I.* AU - Santoni, A.* AU - Sanz, R.B.* AU - Saresella, M.* AU - Sautes-Fridman, C.* AU - Sawitzki, B.* AU - Schadt, L.* AU - Scheffold, A.* AU - Scherer, H.U.* AU - Schiemann, M.* AU - Schildberg, F.A.* AU - Schimisky, E.* AU - Schlitzer, A.* AU - Schlosser, J.* AU - Schmid, S.* AU - Schmitt, S.* AU - Schober, K.* AU - Schraivogel, D.* AU - Schuh, W.* AU - Schüler, T.* AU - Schulte, R.* AU - Schulz, A.R.* AU - Schulz, S.R.* AU - Scottá, C.* AU - Scott-Algara, D.* AU - Sester, D.P.* AU - Shankey, T.V.* AU - Silva-Santos, B.* AU - Simon, A.K.* AU - Sitnik, K.M.* AU - Sozzani, S.* AU - Speiser, D.E.* AU - Spidlen, J.* AU - Stahlberg, A.* AU - Stall, A.M.* AU - Stanley, N.* AU - Stark, R.* AU - Stehle, C.* AU - Steinmetz, T.* AU - Stockinger, H.* AU - Takahama, Y.* AU - Takeda, K.* AU - Tan, L.* AU - Tárnok, A.* AU - Tiegs, G.* AU - Toldi, G.* AU - Tornack, J.* AU - Traggiai, E.* AU - Trebak, M.* AU - Tree, T.I.M.* AU - Trotter, J.* AU - Trowsdale, J.* AU - Tsoumakidou, M.* AU - Ulrich, H.* AU - Urbanczyk, S.* AU - van de Veen, W.* AU - van den Broek, M.* AU - van der Pol, E.* AU - Van Gassen, S.* AU - Van Isterdael, G.* AU - van Lier, R.A.W.* AU - Veldhoen, M.* AU - Vento-Asturias, S.* AU - Vieira, P.* AU - Voehringer, D.* AU - Volk, H.D.* AU - von Borstel, A.* AU - von Volkmann, K.* AU - Waisman, A.* AU - Walker, R.V.* AU - Wallace, P.K.* AU - Wang, S.A.* AU - Wang, X.M.* AU - Ward, M.D.* AU - Ward-Hartstonge, K.A.* AU - Warnatz, K.* AU - Warnes, G.* AU - Warth, S.* AU - Waskow, C.* AU - Watson, J.V.* AU - Watzl, C.* AU - Wegener, L.* AU - Weisenburger, T.* AU - Wiedemann, A.* AU - Wienands, J.* AU - Wilharm, A.* AU - Wilkinson, R.J.* AU - Willimsky, G.* AU - Winkelmann, R.* AU - Wong, A.* AU - Wurst, P.* AU - Yang, J.H.M.* AU - Yang, J.* AU - Yazdanbakhsh, M.* AU - Yu, L.* AU - Yue, A.* AU - Zhang, H.* AU - Zhao, Y.* AU - Ziegler, S.M.* AU - Zielinski, C.* AU - Zimmermann, J.* AU - Zychlinsky, A.* C1 - 57151 C2 - 47613 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1457-1973 TI - Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). JO - Eur. J. Immunol. VL - 49 IS - 10 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - de Jong, R.J. AU - Alessandrini, F. AU - Wimmer, M. AU - Maier, A.-M. AU - Zimmermann, E. AU - Buters, J.T.M. AU - Schmidt-Weber, C.B. AU - Esser-von Bieren, J. AU - Ohnmacht, C. C1 - 57064 C2 - 47518 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 192-193 TI - The aryl hydrocarbon receptor and its's downstream target cytochrome P450 member CYP1B1 regulate allergic airway inflammation. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Dimitrov, S. AU - Lange, T.* AU - Gouttefangeas, C.* AU - Jensen, A.T.* AU - Szczepanski, M.* AU - Lehnholz, J.* AU - Soekadar, S.* AU - Rammensee, H.G.* AU - Born, J. AU - Besedovsky, L.* C1 - 57084 C2 - 47476 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 228-228 TI - G alpha(s)-coupled receptor agonists suppress, whereas sleep promotes integrin activation on antigen-specific T cells in humans. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AB - Allergen specific tolerance induction efficiently ameliorates subsequent allergen induced inflammatory responses. The underlying regulatory mechanisms have been attributed mainly to interleukin (IL)-10 produced by diverse hematopoietic cells, while targets of IL-10 in allergen specific tolerance induction have not yet been well defined. Here, we investigate potential cellular targets of IL-10 in allergen specific tolerance induction using mice with a cell type specific inactivation of the IL-10 receptor gene. Allergic airway inflammation was effectively prevented by tolerance induction in mice with IL-10 receptor (IL-10R) deficiency in T or B cells. Similarly, IL-10R on monocytes/macrophages and/or neutrophils was not required for tolerance induction. In contrast, tolerance induction was impaired in mice that lack IL-10R on dendritic cells: those mice developed an allergic response characterized by a pronounced neutrophilic lung infiltration, which was not ameliorated by tolerogenic treatment. In conclusion, our results show that allergen specific tolerance can be effectively induced without a direct impact of IL-10 on cells of the adaptive immune system, and highlight dendritic cells, but not macrophages nor neutrophils, as the main target of IL-10 during tolerance induction. AU - Dolch, A.* AU - Kunz, S.* AU - Dorn, B.* AU - Alessandrini, F. AU - Müller, W.* AU - Jack, R.S.* AU - Martin, S.F.* AU - Roers, A.* AU - Jakob, T.* C1 - 55005 C2 - 46065 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 302-312 TI - IL-10 signaling in dendritic cells is required for tolerance induction in a murine model of allergic airway inflammation. JO - Eur. J. Immunol. VL - 49 IS - 2 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Friedl, A. AU - Angioni, C.* AU - Thomas, D.* AU - Haimerl, P. AU - Schmidt-Weber, C.B. AU - Esser-von Bieren, J. C1 - 57066 C2 - 47520 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 64-64 TI - Repeated exposure to house dust mite drives persistent activation of inflammatorymacrophages. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Geiselhöringer, A.-L. AU - Potthast, M. AU - Andreas, N.* AU - Garg, G.* AU - de Jong, R.J. AU - Riewaldt, J.* AU - Russkamp, D. AU - Riemann, M.* AU - Girard, J.P.* AU - Blank, S. AU - Kretschmer, K.* AU - Schmidt-Weber, C.B. AU - Korn, T.* AU - Weih, F.* AU - Ohnmacht, C. C1 - 57083 C2 - 47475 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 52-53 TI - Accumulation of tissue Tregs due to dendritic cell specific ablation of ReIB protects from autoimmune inflammation. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Hagl, B. AU - Spielberger, B.D. AU - Effner, R. AU - Notheis, G.* AU - Meitinger, T. AU - Renner, E.D. C1 - 57060 C2 - 47514 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 190-191 TI - Lessons to learn from primary immunodeficiencies overlapping with atopic eczema. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Haimerl, P. AU - Bernhard, U. AU - Chaker, A.M.* AU - Zissler, U.M. AU - Pastor, X. AU - Cecil, A. AU - Schindela, S. AU - Prehn, C. AU - Schmidt-Weber, C.B. AU - Esser-von Bieren, J. C1 - 57055 C2 - 47482 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 200-200 TI - Lipid metabolism and macrophage activation are broadly dysregulated in aspirin-exacerbated respiratory disease. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Henkel, F. AU - Friedl, A. AU - Haid, M. AU - Thomas, D.* AU - Bouchery, T.* AU - Haimerl, P. AU - Alessandrini, F. AU - Jimenez, M.d.l.R. AU - Harris, N.* AU - Schmidt-Weber, C.B. AU - Adamski, J. AU - Esser-von Bieren, J. C1 - 57059 C2 - 47513 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 235-236 TI - House dust mite drives proinflammatory eicosanoid reprogramming and macrophage effector functions. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Hollaus, A. AU - Martin, L.K. AU - Moosmann, A. C1 - 57049 C2 - 47488 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 130-130 TI - Targets of the T cell response to human herpesvirus 6B. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Huth, A. AU - Liang, X. AU - Krebs, S.* AU - Blum, H.* AU - Moosmann, A. C1 - 57069 C2 - 47497 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 112-112 TI - The antigen-specific T-cell receptor repertoire against human cytomegalovirus. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Kreft, L. AU - Meng, C.* AU - Bachler, B.* AU - Kleigrewe, K.* AU - Basic, M.* AU - Stecher, B.* AU - Bleich, A.* AU - Ohnmacht, C. C1 - 57081 C2 - 47473 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 135-136 TI - Use of gnotobiotic mouse models to reveal a microbial impact on intestinal immune tolerance. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Kureha, T. AU - Borland, K.* AU - Koenig, J.* AU - Kellner, S.* AU - Heissmeyer, V. C1 - 57067 C2 - 47521 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 68-69 TI - m6A deficiency on mRNAs by T cell-specific depletion of Wtap causes spontaneous colitis. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Lechner, M. AU - Engleitner, T.* AU - Oellinger, R.* AU - Rad, R.* AU - Schmidt-Supprian, M.* AU - Strobl, L.J. AU - Zimber-Strobl, U. C1 - 57074 C2 - 47501 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 25-26 TI - "Two B or not two B?" The potency of Nntch2 in follicular vs marginal zone B cell identity. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Mohr, A.-W. AU - Moosmann, A. C1 - 57050 C2 - 47487 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 99-100 TI - The T cell epitope repertoire of polyomavirus BK. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AB - Antioxidant systems maintain cellular redox homeostasis. The thioredoxin-1 (Trx1) and the glutathione (GSH)/glutaredoxin-1 (Grx1) systems are key players in preserving cytosolic redox balance. In fact, T lymphocytes critically rely on reducing equivalents from the Trx1 system for DNA biosynthesis during metabolic reprogramming upon activation. We here show that the Trx1 system is also indispensable for development and functionality of marginal zone (MZ) B cells and B1 cells in mice. In contrast, development of conventional B cells, follicular B-cell homeostasis, germinal center reactions, and antibody responses are redundantly sustained by both antioxidant pathways. Proliferating B2 cells lacking Txnrd1 have increased glutathione (GSH) levels and upregulated cytosolic Grx1, which is barely detectable in expanding thymocytes. These results suggest that the redox capacity driving proliferation is more robust and flexible in B cells than in T cells, which may have profound implications for the therapy of B and T-cell neoplasms. AU - Muri, J.* AU - Thut, H.* AU - Heer, S.* AU - Krueger, C.C.* AU - Bornkamm, G.W. AU - Bachmann, M.F.* AU - Kopf, M.* C1 - 55571 C2 - 46278 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 709-723 TI - The thioredoxin-1 and glutathione/glutaredoxin-1 systems redundantly fuel murine B-cell development and responses. JO - Eur. J. Immunol. VL - 49 IS - 5 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Musumeci, A.* AU - Lutz, K.* AU - Dursun, E.* AU - Sie, C.* AU - Ziegenhain, C.* AU - Bagnoli, J.* AU - Luecken, M. AU - Korn, T.* AU - Enard, W.* AU - Theis, F.J. AU - Krug, A.* C1 - 57068 C2 - 47523 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 48-48 TI - Identification of a DC precursor population with pDC and cDC potential responding to endosomal TLR stimulation with increased pDC output. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Raj, T.* AU - Zoeller, J.* AU - Hu, D.* AU - Bianco, G.* AU - Heikenwaelder, M.* AU - Heissmeyer, V. C1 - 57065 C2 - 47519 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 62-62 TI - Roquin deficiency in T cells induces early stages of pancreatic cancer. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Rauer, D.* AU - Frank, U. AU - Müller, C. AU - Gilles, S.* AU - Aglas, L.* AU - Ferreira, F.* AU - Ernst, D. AU - Alessandrini, F. AU - Traidl-Hoffmann, C.* C1 - 57052 C2 - 47485 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 131-131 TI - Influence of elevated ambient CO2 on the sensitizing potential of ragweed (Ambrosia artemisiifolia) pollen. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Rausch, L.* AU - Kranich, J.* AU - Chlis, N.-K. AU - Schifferer, M.* AU - Simons, M.* AU - Theis, F.J. AU - Brocker, T.* C1 - 57063 C2 - 47517 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 88-88 TI - Analysis of EV-decorated CD8+T cells during viral infection. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Scheffler, L. AU - Feicht, S. AU - Strobl, L.J. AU - Ehrenberg, S. AU - Baccarini, M.* AU - Bornkamm, G.W. AU - Zimber-Strobl, U. C1 - 57056 C2 - 47481 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 85-85 TI - B-Raf and Raf-1 are dispensable for activation of the MAPK/Erk signaling pathway in murine B cells but contribute to plasma cell differentiation. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Serr, I. C1 - 57051 C2 - 47486 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 7-8 TI - T cell activation versus tolerance induction in islet autoimmunity. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Stutte, S.* AU - Ruf, J.* AU - Kugler, I.* AU - Ishikawa-Ankerhold, H.* AU - Blutke, A. AU - Marconi, P.* AU - Maeda, T.* AU - Kaisho, T.* AU - Krug, A.* AU - Lauterbach, H.* AU - Colonna, M.* AU - von Andrian, U.* AU - Brocker, T.* C1 - 57082 C2 - 47474 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 69-70 TI - Type-I interferon regulates ghrelin-levels leading to anorexia and weight loss while promoting inflammatory immune responses. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Thomas, J. AU - Quaranta, M.* AU - Krause, L. AU - Atenhan, A. AU - Buters, J.T.M. AU - Ohnmacht, C. AU - de Jong, R.J. AU - Schmidt-Weber, C.B. AU - Eyerich, S. C1 - 57054 C2 - 47483 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 282-283 TI - FOXO4 and AHR control a stress-induced immune-mediated host protection via secretion of IL-22. JO - Eur. J. Immunol. VL - 49 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AU - Yamano, T.* AU - Steinert, M.* AU - Steer, B. AU - Klein, L.* AU - Hammerschmidt, W. AU - Adler, H. C1 - 54853 C2 - 45841 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 351-352 TI - B cells latently infected with murine gammaherpesvirus 68 (MHV-68) are present in the mouse thymus-A step toward immune evasion? JO - Eur. J. Immunol. VL - 49 IS - 2 PB - Wiley PY - 2019 SN - 0014-2980 ER - TY - JOUR AB - Obesity and type-2 diabetes (T2D) are associated with metabolic defects and inflammatory processes in fat depots. FoxP3 + regulatory T cells (Tregs) control immune tolerance, and have an important role in controlling tissue-specific inflammation. In this mini-review we will discuss current insights into how cross-talk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases, focusing on the role of CD4 + T cells and Tregs. We will also highlight potential opportunities for how the immunoregulatory properties of Tregs could be harnessed to control inflammation in obesity and T2D and emphasize the critical need for more research on humans to establish mechanisms that are conserved in both mice and humans. AU - Becker, M. AU - Levings, M.K.* AU - Daniel, C. C1 - 52047 C2 - 43661 CY - Hoboken SP - 1867-1874 TI - Adipose-tissue regulatory T cells: Critical players in adipose-immune crosstalk. JO - Eur. J. Immunol. VL - 47 IS - 11 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AB - Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell-specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL-1β production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis-associated cancer (CAC) model. Card9 -/- mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL-1β generation and defective IL-1β controlled IL-22 production from group 3 innate lymphoid cells. Consistent with the key role of immune-derived IL-22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9 -/- mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9-controlled, ILC3-mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9-mediated innate immunity in inflammation-associated carcinogenesis. AU - Bergmann, H.* AU - Roth, S.* AU - Pechloff, K.* AU - Kiss, E.A.* AU - Kühn, S.* AU - Heikenwälder, M. AU - Diefenbach, A.* AU - Greten, F.R.* AU - Ruland, J.* C1 - 51539 C2 - 43297 CY - Hoboken SP - 1342-1353 TI - Card9-dependent IL-1β regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer. JO - Eur. J. Immunol. VL - 47 IS - 8 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AU - Cossarizza, A.* AU - Chang, H.D.* AU - Radbruch, A.* AU - Andrä, I.* AU - Annunziato, F.* AU - Bacher, P.* AU - Barnaba, V.* AU - Battistini, L.* AU - Bauer, W.M.* AU - Baumgart, S.* AU - Becher, B.* AU - Beisker, W. AU - Berek, C.* AU - Blanco, A.* AU - Borsellino, G.* AU - Boulais, P.E.* AU - Brinkman, R.R.* AU - Büscher, M.* AU - Busch, D.H.* AU - Bushnell, T.P.* AU - Cao, X.* AU - Cavani, A.* AU - Chattopadhyay, P.K.* AU - Cheng, Q.* AU - Chow, S.* AU - Clerici, M.* AU - Cooke, A.* AU - Cosma, A.* AU - Cosmi, L.* AU - Cumano, A.* AU - Dang, V.D.* AU - Davies, D.* AU - De Biasi, S.* AU - Del Zotto, G.* AU - Della Bella, S.* AU - Dellabona, P.* AU - Deniz, G.* AU - Dessing, M.* AU - Diefenbach, A.* AU - di Santo, J.* AU - Dieli, F.* AU - Dolf, A.* AU - Donnenberg, V.S.* AU - Dörner, T.* AU - Ehrhardt, G.R.A.* AU - Endl, E.* AU - Engel, P.* AU - Engelhardt, B.* AU - Esser, C.* AU - Everts, B.* AU - Falk, C.S.* AU - Fehniger, T.A.* AU - Filby, A.* AU - Fillatreau, S.* AU - Follo, M.* AU - Förster, I.* AU - Foster, J.* AU - Foulds, G.A.* AU - Frenette, P.S.* AU - Galbraith, D.* AU - Garbi, N.* AU - García-Godoy, M.D.* AU - Ghoreschi, K.* AU - Gibellini, L.* AU - Goettlinger, C.* AU - Goodyear, C.S.* AU - Gori, A.* AU - Grogan, J.* AU - Gross, M.* AU - Grützkau, A.* AU - Grummitt, D.* AU - Hahn, J.* AU - Hammer, Q.* AU - Hauser, A.E.* AU - Haviland, D.L.* AU - Hedley, D.* AU - Herrera, G.* AU - Hermann, M.* AU - Hiepe, F.* AU - Holland, T.* AU - Hombrink, P.* AU - Houston, J.P.* AU - Hoyer, B.F.* AU - Huang, B.* AU - Hunter, C.A.* AU - Iannone, A.G.* AU - Jäck, H.M.* AU - Jávega, B.* AU - Jonjic, S.* AU - Juelke, K.* AU - Jung, S.* AU - Kaiser, T.* AU - Kalina, T.* AU - Keller, B.* AU - Khan, S.* AU - Kienhöfer, D.* AU - Kroneis, T.* AU - Kunkel, D.* AU - Kurts, C.* AU - Kvistborg, P.* AU - Lannigan, J.* AU - Lantz, O.* AU - Larbi, A.* AU - LeibundGut-Landmann, S.* AU - Leipold, M.D.* AU - Levings, M.K.* AU - Litwin, V.* AU - Liu, Y.* AU - Lohoff, M.* AU - Lombardi, G.* AU - Lopez, L.* AU - Lovett-Racke, A.* AU - Lubberts, E.* AU - Ludewig, B.* AU - Lugli, E.* AU - Maecker, H.T.* AU - Martrus, G.* AU - Matarese, G.* AU - Maueröder, C.* AU - McGrath, M.* AU - McInnes, I.* AU - Mei, H.E.* AU - Melchers, F.* AU - Melzer, S.* AU - Mielenz, D.* AU - Mills, K.* AU - Mjösberg, J.* AU - Moore, J.C.* AU - Moran, B.* AU - Moretta, A.* AU - Moretta, L.* AU - Mosmann, T.R.* AU - Müller, S.* AU - Müller, W.* AU - Münz, C.* AU - Multhoff, G. AU - Munoz, L.E.* AU - Murphy, K.M.* AU - Nakayama, T.* AU - Nasi, M.* AU - Neudörfl, C.* AU - Nolan, J.J.* AU - Nourshargh, S.* AU - O'Connor, J.E.* AU - Ouyang, W.* AU - Oxenius, A.* AU - Palankar, R.* AU - Panse, I.* AU - Peterson, P.* AU - Peth, C.* AU - Petriz, J.* AU - Philips, D.H.* AU - Pickl, W.* AU - Piconese, S.* AU - Pinti, M.* AU - Pockley, A.G.* AU - Podolska, M.J.* AU - Pucillo, C.* AU - Quataert, S.A.* AU - Radstake, T.R.D.J.* AU - Rajwa, B.* AU - Rebhahn, J.A.* AU - Recktenwald, D.* AU - Remmerswaal, E.B.M.* AU - Rezvani, K.* AU - Rico, L.G.* AU - Robinson, J.P.* AU - Romagnani, C.* AU - Rubartelli, A.* AU - Ruland, J.* AU - Sakaguchi, S.* AU - Sala-de-Oyanguren, F.* AU - Samstag, Y.* AU - Sanderson, S.* AU - Sawitzki, B.* AU - Scheffold, A.* AU - Schiemann, M.* AU - Schildberg, F.* AU - Schimisky, E.* AU - Schmid, S.A.* AU - Schmitt, S.* AU - Schober, K.* AU - Schüler, T.* AU - Schulz, A.R.* AU - Schumacher, T.* AU - Scottà, C.* AU - Shankey, T.V.* AU - Shemer, A.* AU - Simon, A.K.* AU - Spidlen, J.* AU - Stall, A.M.* AU - Stark, R.* AU - Stehle, C.* AU - Stein, M.M.* AU - Steinmetz, T.* AU - Stockinger, H.* AU - Takahama, Y.* AU - Tarnok, A.* AU - Tian, Z.* AU - Toldi, G.* AU - Tornack, J.* AU - Traggiai, E.* AU - Trotter, J.* AU - Ulrich, H.* AU - van der Braber, M.* AU - van Lier, R.A.W.* AU - Veldhoen, M.* AU - Vento-Asturias, S.* AU - Vieira, P.* AU - Voehringer, D.* AU - Volk, H.D.* AU - von Volkmann, K.* AU - Waisman, A.* AU - Walker, R.* AU - Ward, M.D.* AU - Warnatz, K.* AU - Warth, S.* AU - Watson, J.V.* AU - Watzl, C.* AU - Wegener, L.* AU - Wiedemann, A.* AU - Wienands, J.* AU - Willimsky, G.* AU - Wing, J.B.* AU - Wurst, P.* AU - Yu, L.* AU - Yue, A.* AU - Zhang, Q.* AU - Zhao, Y.* AU - Ziegler, S.* AU - Zimmermann, J.* C1 - 52094 C2 - 43721 CY - Hoboken SP - 1584-1797 TI - Guidelines for the use of flow cytometry and cell sorting in immunological studies. JO - Eur. J. Immunol. VL - 47 IS - 10 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AU - Jung, S. AU - Bauer, S.* C1 - 52668 C2 - 44445 CY - Hoboken SP - 79-79 TI - RIG I senses ribosomal RNA derived degradation products. JO - Eur. J. Immunol. VL - 47 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AU - Kallin, N.* AU - Bosch, M.* AU - Manske, K.* AU - Protzer, U. AU - Wohlleber, D.* AU - Knolle, P.A.* C1 - 52666 C2 - 44453 CY - Hoboken SP - 83-83 TI - Exhaustion of virus-specific CXCR6+liver-resident memory CD8 T cells during persistent liver infection. JO - Eur. J. Immunol. VL - 47 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AB - Schistosomiasis is a non-transplacental helminth infection. Chronic infection during pregnancy suppresses allergic airway responses in offspring. We addressed the question whether in utero exposure to chronic schistosome infection (Reg phase) in mice affects B cell and T cell development. Therefore, we focused our analysis on T cell differentiation capacity induced by epigenetic changes in promoter regions of signature cytokines in offspring. Here we show that naïve T cells from offspring of schistosome infected female mice had a strong capacity to differentiate into TH 1 cells, whereas TH 2 differentiation was impaired. In accordance, reduced levels of histone acetylation of the IL-4 promoter regions were observed in naïve T cells. To conclude, our mouse model revealed distinct epigenetic changes within the naïve T cell compartment affecting TH 2 and TH 1 cell differentiation in offspring of mothers with chronic helminth infection. These findings could eventually help understand how helminths alter T cell driven immune responses induced by allergens, bacterial or viral infections, as well as vaccines. AU - Klar, K.* AU - Perchermeier, S.* AU - Bhattacharjee, S.* AU - Harb, H.* AU - Adler, T. AU - Istvanffy, R.* AU - Loffredo-Verde, E.* AU - Oostendorp, R.* AU - Renz, H.* AU - Prazeres da Costa, C.U.* C1 - 50677 C2 - 42833 CY - Hoboken SP - 841-847 TI - Chronic schistosomiasis during pregnancy epigenetically reprograms T cell differentiation in offspring of infected mothers. JO - Eur. J. Immunol. VL - 47 IS - 5 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AU - Kurz, S.* AU - Janas, M.K.* AU - Schneider, A.* AU - Lohr, K.* AU - Wettmarshausen, J.* AU - Perocchi, F. AU - Knolle, P.A.* AU - Wohlleber, D.* C1 - 52667 C2 - 44452 CY - Hoboken SP - 186-186 TI - Linking TNF receptor signaling in virus-infected hepatocytes to cell death for immune control of liver infection. JO - Eur. J. Immunol. VL - 47 PB - Wiley PY - 2017 SN - 0014-2980 ER - TY - JOUR AB - Regulatory mechanisms initiated by allergen specific immunotherapy are mainly attributed to T cell-derived IL-10. However, it has not been shown that T cell-derived IL-10 is required for successful tolerance induction. Here, we analyze cellular sources and the functional relevance of cell type specific IL-10 during tolerance induction in a murine model of allergic airway inflammation. While tolerance induction was effective in IL-10 competent mice, neutralizing IL-10 prior to tolerogenic treatment completely abrogated the beneficial effects. Cellular sources of IL-10 during tolerance induction were identified by using transcriptional reporter mice as T cells, B cells and to a lesser extent DCs. Interestingly, tolerance induction was still effective in mice with T cell-, B cell-, B and T cell- or DC-specific IL-10 deficiency. In contrast, tolerance induction was not possible in mice lacking IL-10 in all hematopoetic cells, while it was effective in bone marrow chimera that lacked IL-10 only in non-hematopoetic cells. Taken together, allergen specific tolerance depends on IL-10 from hematopoetic sources. The beneficial effects of allergen specific immunotherapy cannot solely be attributed to IL-10 from T cells, B cells or even DCs, suggesting a high degree of cellular redundancy in IL-10 mediated tolerance. AU - Kunz, S.* AU - Preuhsler, A.* AU - Surianarayanan, S.* AU - Dorn, B.* AU - Bewersdorff, M. AU - Alessandrini, F. AU - Behrendt, R.* AU - Karp, C.L.* AU - Müller, W.* AU - Martin, S.F.* AU - Roers, A.* AU - Jakob, T.* C1 - 48794 C2 - 41333 CY - Hoboken SP - 2018-2027 TI - T cell derived IL-10 is dispensable for tolerance induction in a murine model of allergic airway inflammation. JO - Eur. J. Immunol. VL - 46 IS - 8 PB - Wiley-blackwell PY - 2016 SN - 0014-2980 ER - TY - JOUR AU - Rincon-Orozco, B.* AU - Higareda, J. AU - Rabinovich, G.A.* C1 - 49789 C2 - 40928 CY - Hoboken SP - 189-189 TI - System-level effects of ectopic galectin-7 reconstitution in cervical cancer and their microenvironment. JO - Eur. J. Immunol. VL - 46 PB - Wiley-blackwell PY - 2016 SN - 0014-2980 ER - TY - JOUR AU - Tao, S.* AU - Tao, R.* AU - Patra, M. AU - Drexler, I. C1 - 50463 C2 - 42258 SP - 339-339 TI - The subcellular localization of viral antigen after infection shapes the antigenic profile and protective capacity of poxvirus-mediated T cell immunity. JO - Eur. J. Immunol. VL - 46 PY - 2016 SN - 0014-2980 ER - TY - JOUR AU - Tomas, L.* AU - Björkbacka, H.* AU - Edsfeldt, A.* AU - Danielsson, A.* AU - Wigren, M.* AU - Grufman, H.* AU - Persson, A.* AU - Prehn, C. AU - Adamski, J. AU - Nilsson, J.* AU - Gonçalves, I.* C1 - 49791 C2 - 40929 CY - Hoboken SP - 445-445 TI - A lipid metabolite profile in atherosclerotic plaques associated with increased inflammation and cardiovascular risk. JO - Eur. J. Immunol. VL - 46 PB - Wiley-blackwell PY - 2016 SN - 0014-2980 ER - TY - JOUR AU - Wildner, G.* AU - Diedrichs-Moehring, M.* AU - Kaufmann, U.* AU - von Toerne, C. AU - Kungl, A.* AU - Thurau, S.R.* C1 - 49793 C2 - 40936 CY - Hoboken SP - 907-907 TI - Immune mechanisms in chronic or relapsing autoimmune diseases investigated in the experimental rat model of autoimmune uveitis (EAU). JO - Eur. J. Immunol. VL - 46 PB - Wiley-blackwell PY - 2016 SN - 0014-2980 ER - TY - JOUR AB - Little is known on the control of lymphomas by NK cells. Here, we study the role of the NK group 2D (NKG2D) receptor for the immunosurveillance of lymphoma. By using transplantable tumors as well as a λ-myc-transgenic model of endogenously arising lymphoma and NKG2D-deficient mice, we show that NK cells eliminate tumor cells in vivo after receiving two signals. One step involved the activation of NK cells giving rise to IFN-γ expression, which was effected by MHCI(low) tumor cells or DCs. However, this was necessary but not sufficient to mediate cytotoxicity. Triggering cytotoxicity additionally required a second step, which could be mediated by engagement of the NKG2D receptor. Thus, NKG2D-deficient NK cells could become activated in vivo, but they were not able to reject transplanted lymphomas or to degranulate in animals bearing autochthonous lymphomas. Tumor growth in NKG2D-deficient λ-myc-transgenic mice was significantly accelerated compared to NKG2D-competent animals. Whereas the latter developed tumors that lost expression of NKG2D ligands (NKG2D-L) in late disease stages, this did not occur in NKG2D-deficient mice. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D-L loss mutants provides a mechanism of tumor escape. AU - Belting, L. AU - Hömberg, N. AU - Przewoznik, M. AU - Brenner, C. AU - Riedel, T. AU - Flatley, A. AU - Polic, B.* AU - Busch, D.H.* AU - Röcken, M.* AU - Mocikat, R. C1 - 46292 C2 - 37494 SP - 2593-2601 TI - Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma. JO - Eur. J. Immunol. VL - 45 IS - 9 PY - 2015 SN - 0014-2980 ER - TY - JOUR AB - Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation. AU - Haftmann, C.* AU - Stittrich, A.B.* AU - Zimmermann, J.* AU - Fang, Z.* AU - Hradilkova, K.* AU - Bardua, M.* AU - Westendorf, K.* AU - Heinz, G.A. AU - Riedel, R.* AU - Siede, J.* AU - Lehmann, K.* AU - Weinberger, E.E.* AU - Zimmel, D.* AU - Lauer, U.M.* AU - Häupl, T.* AU - Sieper, J.* AU - Backhaus, M.* AU - Neumann, C.* AU - Hoffmann, U.* AU - Porstner, M.* AU - Chen, W.* AU - Grün, J.R.* AU - Baumgrass, R.* AU - Matz, M.* AU - Löhning, M.* AU - Scheffold, A.* AU - Wittmann, J.* AU - Chang, H.* AU - Rajewsky, N.* AU - Jack, H.M.* AU - Radbruch, A.H.* AU - Mashreghi, M.F.* C1 - 44435 C2 - 36915 CY - Hoboken SP - 1192-1205 TI - MiR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim. JO - Eur. J. Immunol. VL - 45 IS - 4 PB - Wiley-blackwell PY - 2015 SN - 0014-2980 ER - TY - JOUR AB - The NLR protein, NLRC5, is an important regulator of MHC I gene expression, however, the role of NLRC5 in other innate immune responses is less well defined. In the present study, we report that NLRC5 binds RIG-I and that this interaction is critical for robust antiviral responses against influenza virus. Overexpression of NLRC5 in the human lung epithelial cell line, A549, and normal human bronchial epithelial (NHBE) cells resulted in impaired replication of influenza virus A/Puerto Rico/8/34 virus (PR8) and enhanced IFN-β expression. Influenza virus leads to induction of IFN-β that drives RIG-I and NLRC5 expression in host cells. Our results suggest that NLRC5 extends and stabilizes influenza virus-induced RIG-I expression and delays expression of the viral inhibitor protein NS1. We show that NS1 binds to NLRC5 to suppress its function. Interaction domain mapping revealed that NLRC5 interacts with RIG-I via its N-terminal death domain and that NLRC5 enhanced antiviral activity in a LRR-domain-independent manner. Taken together, our findings identify a novel role for NLRC5 in RIG-I-mediated antiviral host responses against influenza virus infection, distinguished from the role of NLRC5 in MHC class I gene regulation. AU - Ranjan, P.* AU - Singh, N.* AU - Kumar, A.* AU - Neerincx, A.* AU - Kremmer, E. AU - Cao, W.* AU - Davis, W.G.* AU - Katz, J.M.* AU - Gangappa, S.* AU - Lin, R.* AU - Kufer, T.A.* AU - Sambhara, S.* C1 - 42818 C2 - 35347 CY - Hoboken SP - 758-772 TI - NLRC5 interacts with RIG-I to induce a robust antiviral response against influenza virus infection. JO - Eur. J. Immunol. VL - 45 IS - 3 PB - Wiley-blackwell PY - 2015 SN - 0014-2980 ER - TY - JOUR AU - Adler, H. AU - Steer, B. AU - Juskewitz, E.* AU - Kammerer, R.* C1 - 31714 C2 - 34695 CY - Hoboken SP - 2521-2522 TI - To the editor: Murine gammaherpesvirus 68 (MHV-68) escapes from NK-cell-mediated immune surveillance by a CEACAM1-mediated immune evasion mechanism. JO - Eur. J. Immunol. VL - 44 IS - 8 PB - Wiley-blackwell PY - 2014 SN - 0014-2980 ER - TY - JOUR AB - AOC3 (Amine oxidase, copper containing 3, also known as vascular adhesion protein-1 (VAP-1)) is an endothelial adhesion molecule that contributes to the extravasation of neutrophils, macrophages and lymphocytes to sites of inflammation. However, the role of AOC3/VAP-1 in allergic responses remains unknown. Here we studied eosinophil and CD4+ T-cell recruitment to the airways using AOC3/VAP-1-deficient mice. In an OVA-triggered asthma model, AOC3/VAP-1 slightly contributed to the accumulation of leukocytes in lungs in an age-dependent manner. We then established a new model to kinetically measure recruitment of OVA-specific CD4+ T cells to different airway immune compartments during the priming and effector phases of an adaptive immune response. The results showed that in the absence of AOC3/VAP-1, recruitment of antigen-specific CD4+ T cells to draining bronchial lymph nodes is reduced by 89% on day 3 after tracheal allergen exposure, but this difference was not observed on day 6. The dispersal of effector cells to lung and tracheal mucosa is AOC3/VAP-1-independent. Thus, in allergic airway reactions, AOC3/VAP-1 transiently contributes to the antigen-specific, CD4+ T-cell traffic to secondary lymphatic tissues, but not to airway mucosa or lung parenchyma. Our results suggest a largely redundant function for AOC3/VAP-1 in allergic inflammatory responses of the airways. AU - Dunkel, J.* AU - Aguilar-Pimentel, J.A. AU - Ollert, M. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Hrabě de Angelis, M. AU - Jalkanen, S.* AU - Salmi, M.* AU - Veres, T.Z.* C1 - 31951 C2 - 34894 SP - 3232-3239 TI - Endothelial amine oxidase AOC3 transiently controbutes to adaptive immune responses in the airways. JO - Eur. J. Immunol. VL - 44 IS - 11 PY - 2014 SN - 0014-2980 ER - TY - JOUR AB - T helper (Th) cells are important mediators of adaptive immunity and involved in various diseases. During the past decade, the Th family has expanded from including Th1 and Th2 cells to also encompass Th9, Th17, Th22 and Treg cells; the original classification using the expression of signature cytokines is still the gold standard for definition of subset affiliation. However, the identification of Th cells that do not fit into these tight conceptual boundaries has tumbled the field into an identity crisis. This review gives an overview on different Th-cell classification approaches, their advantages and drawbacks. In addition, this review highlights the functional properties of distinct Th subsets and their effector cytokines in tissues and disease-specific settings with a special focus on inflammatory skin diseases. AU - Eyerich, S. AU - Zielinski, E.C.* C1 - 32411 C2 - 35091 SP - 3475-3483 TI - Defining Th-cell subsets in a classical and tissue-specific manner: Examples from the skin. JO - Eur. J. Immunol. VL - 44 IS - 12 PY - 2014 SN - 0014-2980 ER - TY - JOUR AB - Peptides presented on major histocompatibility complex (MHC) class I molecules are generated via cytosolic proteolysis. However, the nature of the endogenous peptide precursors and the intracellular processing steps preceding protein degradation remain poorly defined. Here, we assessed whether ubiquitination is an essential signal for proteasomal cleavage of antigen substrates in human cells. Conversion into antigenic peptides occurred in the absence of any detectable N-terminal ubiquitination of the model antigens, and did not require the presence of any of the four types, nor a minimum number of ubiquitinatable amino acids within the antigen substrate. However, the knockdown of ubiquitin, expression of a lysine 48 (K48) ubiquitin mutant, or inhibition of proteasome-associated deubiquitinases significantly impaired antigen presentation. The results presented here are consistent with a model in which the binding of the antigen substrate by an adaptor protein leads to its K48-polyubiquitination and the subsequent delivery of the antigen cargo for degradation by the 26S proteasome. Altogether, these findings show an important but indirect role of K48-polyubiquitination in pre-proteasomal antigen sampling. AU - Fiebiger, B.M. AU - Pfister, H. AU - Behrends, U. AU - Mautner, J. C1 - 43051 C2 - 35956 CY - Hoboken SP - 716-727 TI - Polyubiquitination of lysine-48 is an essential but indirect signal for MHC Class I antigen processing. JO - Eur. J. Immunol. VL - 45 IS - 3 PB - Wiley-blackwell PY - 2014 SN - 0014-2980 ER - TY - JOUR AB - Immunity to tumor differentiation antigens, such as melanoma antigen recognized by T cells 1 (MART-1), has been comprehensively studied. Intriguingly, CD8+ T cells specific for the MART-126(27)-35 epitope in the context of HLA-A0201 are about 100 times more abundant compared with T cells specific for other tumor-associated antigens. Moreover, MART-1-specific CD8+ T cells show a highly biased usage of the Vα-region gene TRAV12-2. Here, we provide independent support for this notion, by showing that the combinatorial pairing of different TCRα- and TCRβ -chains derived from HLA-A2- MART-126-35-specific CD8+ T-cell clones is unusually permissive in conferring MART-1 specificity, provided the CDR1a TRAV12-2 region is used. Whether TCR bias alone accounts for the unusual abundance of HLA-A2-MART-126-35-specific CD8+ T cells has remained conjectural. Here, we provide an alternative explanation: misinitiated transcription of the MART-1 gene resulting in truncated mRNA isoforms leads to lack of promiscuous transcription of the MART-126-35 epitope in human medullary thymic epithelial cells and, consequently, evasion of central self-tolerance toward this epitope. Thus, biased TCR usage and leaky central tolerance might act in an independent and additive manner to confer high frequency of MART-126-35-specific CD8+ T cells. AU - Pinto, S.* AU - Sommermeyer, D.* AU - Michel, C.* AU - Wilde, S. AU - Schendel, D.J. AU - Uckert, W.* AU - Blankenstein, T.* AU - Kyewski, B.* C1 - 32606 C2 - 35193 CY - Hoboken SP - 2811-2821 TI - Misinitiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1-specific T cells. JO - Eur. J. Immunol. VL - 44 IS - 9 PB - Wiley-blackwell PY - 2014 SN - 0014-2980 ER - TY - JOUR AU - Kiss, E.* AU - Eggel, A.* AU - Manel, N.* AU - Eyerich, S. C1 - 28786 C2 - 31927 SP - 1684-1685 TI - 2013 ACTERIA prize winners: Early career scientists who will make a difference. JO - Eur. J. Immunol. VL - 43 IS - 7 PB - Wiley-Blackwell PY - 2013 SN - 0014-2980 ER - TY - JOUR AB - As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1β in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1β in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1-independent IL-1β release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models. AU - Dorhoi, A.* AU - Nouailles, G.* AU - Jörg, S.* AU - Hagens, K.* AU - Heinemann, E.* AU - Pradl, L.* AU - Oberbeck-Müller, D.* AU - Duque-Correa, M.A.* AU - Reece, S.T.* AU - Ruland, J. AU - Brosch, R.* AU - Tschopp, J.* AU - Gross, O.* AU - Kaufmann, S.H.* C1 - 6862 C2 - 29365 SP - 374-384 TI - Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. JO - Eur. J. Immunol. VL - 42 IS - 2 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - The immediate presentation of peptide epitopes on MHC class I (MHC I) after antigen expression has led to the concept that MHC I ligands are mostly derived from defective ribosomal products (DRiPs), a subset of newly synthesized proteins that are rapidly degraded by the proteasome. Whether and to what extent mature proteins contribute to the antigenic pool, however, has remained elusive. Here, we developed a conditional antigen expression system that allows studying antigen presentation from mature proteins by inducing their rapid proteasomal degradation in the absence of further antigen synthesis. Target cells in which expression of two Epstein-Barr virus (EBV) antigens was induced were rapidly recognized by antigen-specific CD8(+) T cells in a time- and dosage-dependent manner, demonstrating that antigen presentation was linked to antigen synthesis. By contrast, T cells failed to recognize target cells containing large amounts of mature protein even after induction of their rapid proteasomal degradation. Thus, the presentation of these antigens proved to be strictly dependent on protein synthesis whereas mature proteins failed to furnish the antigenic pool. These results have implications for the design of immunotherapeutic strategies that aim at targeting proteins with increased half-lives and are hence overexpressed in tumors. AU - Fiebiger, B.M. AU - Moosmann, A. AU - Behrends, U. AU - Mautner, J. C1 - 11026 C2 - 30469 SP - 3167-3173 TI - Mature proteins derived from Epstein-Barr virus fail to feed into the MHC class I antigenic pool. JO - Eur. J. Immunol. VL - 42 IS - 12 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - CD16-positive (CD14(++) CD16(+) and CD14(+) CD16(++) ) monocytes have unique features with respect to phenotype and function. We have used transcriptional profiling for comparison of CD16-positive monocytes and classical monocytes. We show herein that 187 genes are greater than fivefold differentially expressed, including 90 genes relevant to immune response and inflammation. Hierarchical clustering of data for monocyte subsets and CD1c(+) myeloid blood dendritic cells (DCs) demonstrate that CD16-positive cells are more closely related to classical monocytes than to DCs. Reverse transcriptase polymerase chain reaction for ten genes with the strongest differential expression confirmed the pattern including a lower messenger RNA level for CD14, CD163, and versican in CD16-positive monocytes. The pattern was similar for CD16-positive monocytes at rest and after exercise mobilization from the marginal pool. By contrast, alveolar macrophages, small sputum macrophages, breast milk macrophages, and synovial macrophages all showed a different pattern. When monocyte-derived macrophages (MDMs) were generated from CD16-positive monocytes by culture with macrophage colony-stimulating factor in vitro, then the MDMs maintained properties of their progeny with lower expression of CD14, CD163, and versican compared with CD14(++) CD16(-) MDMs. Furthermore, CD16-positive MDMs showed a higher phagocytosis for opsonized Escherichia coli. The data demonstrate that CD16-positive monocytes form a distinct type of cell, which gives rise to a distinct macrophage phenotype. AU - Frankenberger, M. AU - Hofer, T.P. AU - Marei, A.* AU - Dayyani, F.* AU - Schewe, S.* AU - Strasser, C.* AU - Aldraihim, A.* AU - Stanzel, F. AU - Lang, R.* AU - Hoffmann, R.* AU - Prazeres da Costa, O.* AU - Buch, T.* AU - Ziegler-Heitbrock, L. C1 - 7417 C2 - 29713 SP - 957-974 TI - Transcript profiling of CD16-positive monocytes reveals a unique molecular fingerprint. JO - Eur. J. Immunol. VL - 42 IS - 4 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - The transcriptional regulator FOXP3 is an important determinant of regulatory T (Treg) cell development and function and is frequently used to quantitate Treg cells. However, FOXP3 is also expressed in recently activated conventional human T cells. Here, we investigated the FOXP3 expression patterns in Treg and activated T cells at a cellular level. Upon activation, human CD4+CD25- T cells expressed FOXP3 mainly in the cytoplasm, in sharp contrast to human CD4+CD25+ Treg cells, where we found FOXP3 to be predominantly expressed in the nucleus. A GFP-FOXP3-fusion protein shuttled from the nucleus to the cytoplasm in transfected primary human T cells. We identified two novel leucine-rich nuclear export signals in FOXP3. Site-directed mutagenesis of both sequences completely abolished nuclear export of FOXP3 in human T cells. Both export sequences localized to exons affected by alternative splicing. The three isoforms FOXP3?2, FOXP3?7, and FOXP3?2?7 localized preferentially to the nucleus. Additionally, forced expression of nucleus-directed FOXP3 induced a Treg-cell-associated gene expression pattern and induced regulatory capacity. These findings should aid in the interpretation of future studies utilizing FOXP3 expression as a Treg-cell marker and shed some light on the molecular mechanisms controlling subcellular FOXP3 localization in human T cells. AU - Magg, T.* AU - Mannert, J.* AU - Ellwart, J.W. AU - Schmid, I.* AU - Albert, M.H.* C1 - 7577 C2 - 29861 SP - 1627-1638 TI - Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells. JO - Eur. J. Immunol. VL - 42 IS - 6 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - The importance of human herpesvirus 6 (HHV-6) species as human pathogens is increasingly appreciated. However, we do not understand how infection is controlled in healthy virus carriers, and why control fails in patients with disease. Other persistent viruses are under continuous surveillance by antigen-specific T cells, and specific T-cell repertoires have been well characterized for some of them. In contrast, knowledge on HHV-6-specific T-cell responses is limited, and missing for CD8+ T cells. Here we identify CD8+ T-cell responses to HHV-6B, the most widespread HHV-6 species, in healthy virus carriers. HHV-6B-specific CD8+ T-cell lines and clones recognized HLA-A2-restricted peptides from the viral structural proteins U54 and U11, and displayed various antigen-specific antiviral effector functions. These CD8+ T cells specifically recognized HHV-6B-infected primary CD4+ T cells in an HLA-restricted manner, produced antiviral cytokines, and killed infected cells, whereas HHV-6A-infected cells were not recognized. Thus, HHV-6B-specific CD8+ T cells are likely to contribute to control of infection, overcoming the immunomodulatory effects exerted by the virus. Potentially, HHV-6-associated disease could be addressed by active or passive immunotherapy that reconstitutes virus-specific CD8+ T-cell responses. AU - Martin, L.K. AU - Schub, A. AU - Dillinger, S. AU - Moosmann, A. C1 - 11446 C2 - 30668 SP - 2901-2912 TI - Specific CD8+ T cells recognize human herpesvirus 6B. JO - Eur. J. Immunol. VL - 42 IS - 11 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - The chemokine receptor CCR7 has a central role in regulating homing and positioning of T cells and DCs to lymph nodes and participates in T-cell development and activation. In this study we addressed the role of CCR7 signaling in T(H) 2 polarization and B-cell activation. We provide evidence that lack of CCR7 drives the capacity of naïve CD4(+) T cells to polarize towards T(H) 2 cells. This propensity contributes to a lymph node environment in CCR7-deficent mice characterized by increased expression of IL-4 and increased frequency of T(H) 2 cells. We show that elevated IL-4 levels lead to B-cell activation characterized by up-regulated expression of MHC class II, CD23 and CD86. Activated B cells are in turn highly efficient in presenting antigen to CD4(+) T cells and thus potentially contribute to the T(H) 2 microenvironment. Taken together, our results support the idea of a CCR7-dependent patterning of T(H) 2 responses, with absent CCR7 signaling favoring T(H) 2 polarization, dislocation of T helper cells into the B-cell follicles and, as a consequence, B-cell activation. AU - Moschovakis, G.L.* AU - Bubke, A.* AU - Dittrich-Breiholz, O.* AU - Braun, A.* AU - Prinz, I.* AU - Kremmer, E. AU - Forster, R.* C1 - 6687 C2 - 29124 SP - 48-57 TI - Deficient CCR7 signaling promotes TH2 polarization and B-cell activation in vivo. JO - Eur. J. Immunol. VL - 42 IS - 1 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - Using N-ethyl-N-nitrosourea-induced mutagenesis, we established a mouse model with a novel form of neutropenia resulting from a point mutation in the transcriptional repressor Growth Factor Independence 1 (Gfi1). These mice, called Genista, had normal viability and no weight loss, in contrast to mice expressing null alleles of the Gfi1 gene. Furthermore, the Genista mutation had a very limited impact on lymphopoiesis or on T- and B-cell function. Within the bone marrow (BM), the Genista mutation resulted in a slight increase of monopoiesis and in a block of terminal granulopoiesis. This block occurred just after the metamyelocytic stage and resulted in the generation of small numbers of atypical CD11b(+) Ly-6G(int) neutrophils, the nuclear morphology of which resembled that of mature WT neutrophils. Unexpectedly, once released from the BM, these atypical neutrophils contributed to induce mild forms of autoantibody-induced arthritis and of immune complex-mediated lung alveolitis. They additionally failed to provide resistance to acute bacterial infection. Our study demonstrates that a hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia characterized by a split pattern of functional responses, reflecting the distinct thresholds required for eliciting neutrophil-mediated inflammatory and anti-infectious responses. AU - Ordoñez-Rueda, D.* AU - Jönsson, F.* AU - Mancardi, D.A.* AU - Zhao, W.* AU - Malzac, A.* AU - Liang, Y.* AU - Bertosio, E.* AU - Grenot, P.* AU - Blanquet, V.* AU - Sabrautzki, S. AU - Hrabě de Angelis, M. AU - Méresse, S.* AU - Duprez, E.* AU - Bruhns, P.* AU - Malissen, B.* AU - Malissen, M.* C1 - 8521 C2 - 30164 SP - 2395-2408 TI - A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia. JO - Eur. J. Immunol. VL - 42 IS - 9 PB - Wiley-VCH PY - 2012 SN - 0014-2980 ER - TY - JOUR AB - T cells exercise their full impact on target cells through a combination of secreted cytokines. The recently described T helper cell subset Th22 is characterized by a combinatorial secretion of IL-22 and TNF-α. Here, we demonstrate that IL-22 increases the TNF-α-dependent induction and secretion of several immune-modulatory molecules such as initial complement factors C1r and C1s, antimicrobial peptides S100A7 and HBD-2 (human β defensin 2), and antimicrobial chemokines CXCL-9/-10/-11 in primary human keratinocytes. The synergism of IL-22 and TNF-α is transmitted intracellularly by MAP kinases and downstream by transcription factors of the AP-1 family. The induction of innate immunity is relevant in an in vitro infection model, where keratinocytes stimulated with Th22 supernatants or recombinant IL-22 plus TNF-α effectively inhibit the growth of Candida albicans and maintain survival of epithelia. Accordingly, the combinatorial stimulation of keratinocytes with IL-22 and TNF-α most efficiently conserves the integrity of the epidermal barrier in a three-dimensional skin infection model as compared with IFN-γ, IL-17, IL-22 or TNF-α alone. In summary, we demonstrate that IL-22 and TNF-α represent a potent, synergistic cytokine combination for cutaneous immunity. AU - Eyerich, S. AU - Wagener, J.* AU - Wenzel, V. AU - Scarponi, C.* AU - Pennino, D. AU - Albanesi, C.* AU - Schaller, M.* AU - Behrendt, H. AU - Ring, J.* AU - Schmidt-Weber, C.B. AU - Cavani, A.* AU - Mempel, M.* AU - Traidl-Hoffmann, C. AU - Eyerich, K. C1 - 6599 C2 - 28960 CY - Weinheim SP - 1894-1901 TI - IL-22 and TNF-α represent a key cytokine combination for epidermal integrity during infection with Candida albicans. JO - Eur. J. Immunol. VL - 41 IS - 7 PB - Wiley-VCH PY - 2011 SN - 0014-2980 ER - TY - JOUR AB - Dominant tolerance to self-antigen requires the presence of sufficient numbers of CD4(+) Foxp3(+) Treg cells with matching antigen specificity. However, the size and role of TCR repertoire diversity for antigen-specific immuno-regulation through Treg cells is not clear. Here, we developed and applied a novel high-throughput (HT) TCR sequencing approach to analyze the TCR repertoire of Treg cells and revealed the importance of high diversity for Treg-cell homeostasis and function. We found that highly polyclonal Treg cells from WT mice vigorously expanded after adoptive transfer into non-lymphopenic TCR-transgenic recipients with low Treg-cell diversity. In that system, we identified specific Treg-cell TCR preferences in distinct anatomic locations such as the mesenteric LN indicating that Treg cells continuously compete for MHC class-II-presented self-, food-, or flora-antigen. Functionally, we showed that high TCR diversity was required for optimal suppressive function of Treg cells in experimental acute graft versus host disease (GvHD). In conclusion, we suggest that efficient immuno-regulation by Treg cells requires high TCR diversity. Thereby, continuous competition of peripheral Treg cells for limited self-antigen shapes an organ-optimized, yet highly diverse, local TCR repertoire. AU - Fohse, L.* AU - Suffner, J.* AU - Suhre, K. AU - Wahl, B.* AU - Lindner, C.* AU - Lee, C.W.* AU - Schmitz, S.* AU - Haas, J.D.* AU - Lamprecht, S.* AU - Koenecke, C.* AU - Bleich, A.* AU - Hämmerling, G.J.* AU - Malissen, B.* AU - Suerbaum, S.* AU - Forster, R.* AU - Prinz, I. C1 - 6917 C2 - 29426 CY - Weinheim SP - 3101-3113 TI - High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells. JO - Eur. J. Immunol. VL - 41 IS - 11 PB - Wiley-VCH PY - 2011 SN - 0014-2980 ER - TY - JOUR AB - Deficiency of transplant recipients for the chemokine receptor CCR7 was originally described to slightly increase the survival time of vascularized solid organ grafts, probably due to a reduced priming of alloreactive T cells. Using a model of allotolerance induction by donor-specific splenocyte transfusion (DST) in combination with anti-CD40L mAb-mediated costimulation blockade (CSB), we show here a striking failure of CCR7-deficient (CCR7(-/-) ) recipients to tolerate cardiac allografts. Furthermore, in addition to the recently described lack of Treg, CCR7(-/-) mice were found to harbor significantly reduced numbers of plasmacytoid dendritic cells (pDCs) within peripheral as well as mesenteric lymph nodes (LNs), but not the bone marrow or spleen. pDCs had previously been suggested to function as tolerogenic APC during allograft transplantation, and a single transfer of syngeneic WT pDCs, but not conventional DCs, was indeed sufficient to rescue graft survival in DST+CSB-treated CCR7(-/-) recipients in a dose-dependent manner. We therefore conclude that the nearly complete absence of pDCs within LNs of CCR7(-/-) mice prevents the successful induction of DST+CSB-mediated allotolerance, leading to the observed acute rejection of cardiac allografts under tolerizing conditions. AU - Liu, X.* AU - Mishra, P.* AU - Yu, S.* AU - Beckmann, J.* AU - Wendland, M.* AU - Kocks, J.* AU - Seth, S.* AU - Hoffmann, K.* AU - Hoffmann, M.* AU - Kremmer, E. AU - Forster, R.* AU - Worbs, T.* C1 - 6240 C2 - 28655 SP - 611-623 TI - Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells. JO - Eur. J. Immunol. VL - 41 IS - 3 PB - Wiley-VCH PY - 2011 SN - 0014-2980 ER - TY - JOUR AB - The molecular mechanisms whereby CD28 alone or associated with TCR can regulate FOXP3 expression are not understood, although the importance of CD28 as a pivotal regulator of CD4(+)CD25(+)FOXP3(+) T cells is well recognized. We previously demonstrated that unique CD28-induced, NF-κB-dependent signals were sufficient to activate FOXP3 transcription in human CD4(+)CD25(-) T cells; however, the exact mechanisms are currently unknown. In this study, we have identified novel κB-binding sites on FOXP3 gene and demonstrated that CD28 signals mediated FOXP3 trans activation by nuclear translocation of RelA/NF-κB and not of c-Rel. The occupancy of FOXP3 κB-binding sites by RelA dimers that correlated with histone acetylation and recruitment of Pol II were required both to initiate FOXP3 transcription and to control the promoter occupancy by NFAT. Interestingly, knockdown of RelA in CD4(+)CD25(-) T cells stimulated through TCR and CD28 significantly affected FOXP3 expression, confirming that also the transcriptional activation of FOXP3 gene by TCR in the presence of CD28-costimulatory signals is RelA-dependent. In conclusion, these data suggest a new mechanism by which FOXP3 is activated and supports the critical role of CD28 in the regulation of peripheral tolerance. AU - Soligo, M.* AU - Camperio, C.* AU - Caristi, S.* AU - Scottà, C.* AU - Porto, P.D.* AU - Costanzo, A.* AU - Mantel, P.Y.* AU - Schmidt-Weber, C.B. AU - Piccolella, E.* C1 - 6035 C2 - 28607 SP - 503-513 TI - CD28 costimulation regulates FOXP3 in a RelA/NF-κB-dependent mechanism. JO - Eur. J. Immunol. VL - 41 IS - 2 PB - Wiley-VCH PY - 2011 SN - 0014-2980 ER - TY - JOUR AB - Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25(+) and CD25(-) Foxp3(+) Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance. AU - Baru, A.M.* AU - Hartl, A.* AU - Lahl, K.* AU - Krishnaswamy, J.K.* AU - Fehrenbach, H.* AU - Yildirim, A.Ö. AU - Garn, H. AU - Renz, H . AU - Behrens, G.M.* AU - Sparwasser, T.* C1 - 3964 C2 - 27465 CY - Weinheim SP - 2259-2266 TI - Selective depletion of Foxp3⁺Treg during sensitization phase aggravates experimental allergic airway inflammation. JO - Eur. J. Immunol. VL - 40 IS - 8 PB - Wiley-VCH PY - 2010 SN - 0014-2980 ER - TY - JOUR AB - The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c-myc-transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D-L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK-cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re-expressed MHC class I and lost NKG2D-L, suggesting a role of these two signals for NK cell-mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D-L levels suggested that NK cell-dependent tumor control required a priming and a triggering signal that were provided by MHC class I down-regulation and by NKG2D-L, respectively. Deleting either of the "two signals" resulted in tumor escape. At early disease stages, immune stimulation through TLR-ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell-dependent manner. Thus, NK-receptor coengagement is crucial for NK-cell functions in vivo and especially for NK cell-mediated tumor surveillance. AU - Brenner, C.D. AU - King, S.B.S. AU - Przewoznik, M. AU - Wolters, I. AU - Adam, C. AU - Bornkamm, G.W. AU - Busch, D.H. AU - Röcken, M.* AU - Mocikat, R. C1 - 46 C2 - 27103 CY - Weinheim SP - 494-504 TI - Requirements for control of B-cell lymphoma by NK cells. JO - Eur. J. Immunol. VL - 40 IS - 2 PB - Wiley-VCH PY - 2010 SN - 0014-2980 ER - TY - JOUR AB - Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCtheta results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-kappaB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-kappaB act downstream of PKCtheta to alter CD8(+) T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-kappaB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCtheta-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCtheta-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-kappaB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCtheta in controlling CD8(+) T-cell anergy induction. AU - Deenick, E.K.* AU - Po, L.* AU - Chapatte, L.* AU - Murakami, K.* AU - Lu, Y.C.* AU - Elford, A.R.* AU - Saibil, S.D.* AU - Ruland, J. AU - Gerondakis, S.* AU - Mak, T.W.* AU - Ohashi, P.S.* C1 - 3420 C2 - 27785 SP - 867-877 TI - c-Rel phenocopies PKCθ but not Bcl-10 in regulating CD8⁺ T-cell activation versus tolerance. JO - Eur. J. Immunol. VL - 40 IS - 3 PB - Wiley-VCH PY - 2010 SN - 0014-2980 ER - TY - JOUR AB - Gammadelta T cells are a potent source of innate IL-17A and IFN-gamma, and they acquire the capacity to produce these cytokines within the thymus. However, the precise stages and required signals that guide this differentiation are unclear. Here we show that the CD24(low) CD44(high) effector gammadelta T cells of the adult thymus are segregated into two lineages by the mutually exclusive expression of CCR6 and NK1.1. Only CCR6+ gammadelta T cells produced IL-17A, while NK1.1+ gammadelta T cells were efficient producers of IFN-gamma but not of IL-17A. Their effector phenotype correlated with loss of CCR9 expression, particularly among the NK1.1+ gammadelta T cells. Accordingly, both gammadelta T-cell subsets were rare in gut-associated lymphoid tissues, but abundant in peripheral lymphoid tissues. There, they provided IL-17A and IFN-gamma in response to TCR-specific and TCR-independent stimuli. IL-12 and IL-18 induced IFN-gamma and IL-23 induced IL-17A production by NK1.1+ or CCR6+ gammadelta T cells, respectively. Importantly, we show that CCR6+ gammadelta T cells are more responsive to TCR stimulation than their NK1.1+ counterparts. In conclusion, our findings support the hypothesis that CCR6+ IL-17A-producing gammadelta T cells derive from less TCR-dependent selection events than IFN-gamma-producing NK1.1+ gammadelta T cells. AU - Haas, J.D.* AU - González, F.H.M.* AU - Schmitz, S. AU - Chennupati, V.* AU - Fohse, L.* AU - Kremmer, E. AU - Forster, R.* AU - Prinz, I.* C1 - 584 C2 - 26708 SP - 3488-3497 TI - CCR6 and NK1.1 distinguish between IL-17A and IFN-γ-producing γδ effector T cells. JO - Eur. J. Immunol. VL - 39 IS - 12 PB - Wiley-VCH PY - 2009 SN - 0014-2980 ER - TY - JOUR AB - The secondary humoral immune response is characterized by plasma B cells secreting isotype-switched and affinity-matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T(FH)) cells, a cell type thought to arise from naive CD4-positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T(FH) cells in their Peyer's patches. This was paralleled by a decreased frequency of T(FH) cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T-cell activation, is down-regulated during T(FH) cell differentiation, resulting in a complete absence of CD226 on those T(FH) cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T(FH) cells. Thus, these cells replace an activating by a putative inhibitory CD155-binding partner during their differentiation. AU - Seth, S.* AU - Ravens, I.* AU - Kremmer, E. AU - Maier, M.K.* AU - Hadis, U.* AU - Hardtke, S.* AU - Forster, R.* AU - Bernhardt, G.* C1 - 1618 C2 - 26851 SP - 3160-3170 TI - Abundance of follicular helper T cells in Peyer's patches is modulated by CD155. JO - Eur. J. Immunol. VL - 39 IS - 11 PB - Wiley-VCH PY - 2009 SN - 0014-2980 ER - TY - JOUR AB - Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg. AU - Heit, A.* AU - Gebhardt, F.* AU - Lahl, K.* AU - Neuenhahn, M.* AU - Schmitz, F.* AU - Anderl, F.* AU - Wagner, H.* AU - Sparwasser, T.* AU - Busch, D.H. AU - Kastenmüller, K. C1 - 1825 C2 - 25607 SP - 1585-1597 TI - Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. JO - Eur. J. Immunol. VL - 38 IS - 6 PB - Wiley-VCH PY - 2008 SN - 0014-2980 ER - TY - JOUR AB - Accumulating evidence suggests that intracellular antigens are endogenously presented on MHC class II, but it is still unknown whether antigens within different subcellular compartments are presented with similar efficiency, and via the same or different pathways. We have previously shown that endogenous MHC class II presentation of the cytosolic bacterial antigen neomycin phosphotransferase II (NeoR) is mediated by autophagy. Here, we addressed whether secluding NeoR from this cytoplasmic pathway by directing the protein into the cell nucleus (NucNeoR) would affect antigen presentation. Unexpectedly, NucNeoR was presented at least as efficiently as the cytosolic version of the antigen. Furthermore, presentation of NucNeoR was also dependent on autophagocytosis and lysosomal processing, indicating that both antigens were presented via the same pathway. Inhibition of CRM1-mediated nuclear export did not impede antigen presentation, indicating that NucNeoR gained access to this autophagy-dependent MHC class II presentation pathway by a CRM1-independent route. Thus, this endogenous presentation pathway broadens the spectrum of intracellular antigens surveyed by CD4(+) T cells by efficiently sampling cytoplasmic as well as nuclear antigens. AU - Riedel, A. AU - Nimmerjahn, F.* AU - Burdach, S.* AU - Behrends, U. AU - Bornkamm, G.W. AU - Mautner, J. C1 - 911 C2 - 25430 SP - 2090-2095 TI - Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1-mediated nuclear export. JO - Eur. J. Immunol. VL - 38 IS - 8 PB - Wiley-VCH PY - 2008 SN - 0014-2980 ER - TY - JOUR AB - Development of autoimmunity is a multi-factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7-deficient mice are prone to develop generalized multi-organ autoimmunity. The autoimmune phenotype of CCR7-/- mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue-specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7-deficient mice show increased susceptibility to streptozotocin-induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity. AU - Davalos-Misslitz, A.C.* AU - Rieckenberg, J.* AU - Willenzon, S.* AU - Worbs, T.* AU - Kremmer, E. AU - Bernhardt, G. AU - Forster, R.* C1 - 3817 C2 - 24801 SP - 613-622 TI - Generalized multi-organ autoimmunity in CCR7-deficient mice. JO - Eur. J. Immunol. VL - 37 IS - 3 PB - Wiley-VCH PY - 2007 SN - 0014-2980 ER - TY - JOUR AB - Compared to "live" vaccines, the immunogenicity of "subunit" vaccines based on recombinant antigen (Ag) is poor, presumably because exogenous Ag fails to effectively access the endosomal Ag-processing pathways of Ag-presenting cells (APC). To overcome this limitation, we exploited biodegradable poly(lactic-co-glycolic) microspheres (MP) co-entrapping Ag and Toll-like receptor (TLR) 9 or 7 ligands as an endosomal delivery device. In vitro, microspheres were rapidly phagocytosed by APC and translocated into phago-endosomal compartments, followed by degradation of the Ag and concurrent activation of endosomal TLR. As a consequence, full maturation of and cytokine secretion by APC as well as Ag-cross-presentation ensued. In vivo, "loaded" microspheres triggered clonal expansion of primary and secondary Ag-specific CD4 and CD8 T cells. The efficacy of CD8 T cell cross-priming was comparable to that of live vectors. The potency of T cell vaccination was demonstrated by protective and therapeutic interventions using infection- and tumor-model systems. These preclinical "subunit" vaccination data thus recommend MP as a generally applicable and powerful endosomal delivery device of exogenous Ag plus TLR-based adjuvants to vaccinate for protective and therapeutic CD4 and CD8 T cell immunity. AU - Heit, A.* AU - Schmitz, F.* AU - Haas, T.* AU - Busch, D.H. AU - Wagner, H.* C1 - 3617 C2 - 25034 SP - 2063-2074 TI - Antigen co-encapsulated with adjuvants efficiently drive protective T cell immunity. JO - Eur. J. Immunol. VL - 37 IS - 8 PB - Wiley-VCH PY - 2007 SN - 0014-2980 ER - TY - JOUR AB - CD155, originally known as the cellular receptor for poliovirus, is the founding member of a subfamily of immunoglobulin-like adhesion receptors. Apart from its function in establishing adherens junctions between contacting epithelial cells, the engagement of CD155 with two recently identified ligands, CD226 and CD96, mediates immunologically relevant processes such as NK cell-driven killing of tumor cells in humans. Here we report on the generation and immunological analysis of mice constitutively deficient of CD155. Moreover, the expression profile of CD155 on hematopoietic cells has been determined using newly established antibodies. CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system. AU - Maier, M.K.* AU - Seth, S.* AU - Czeloth, N.* AU - Qiu, Q.* AU - Ravens, I.* AU - Kremmer, E. AU - Ebel, M.* AU - Müller, W.* AU - Pabst, O.* AU - Forster, R.* AU - Bernhardt, G.* C1 - 3164 C2 - 24809 SP - 2214-2225 TI - The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. JO - Eur. J. Immunol. VL - 37 IS - 8 PB - Wiley-VCH PY - 2007 SN - 0014-2980 ER - TY - JOUR AB - Activation of interferon regulatory factor (IRF)-3 and/or IRF-7 drives the expression of antiviral genes and the production of / IFN, a hallmark of antiviral responses triggered by Toll-like receptors (TLR). Here we describe a novel antiviral signaling pathway operating in myeloid (m) dendritic cells (DC) and macrophages that does not require IRF-3 and/or IRF-7 but is driven by IRF-1. IRF-1 together with myeloid differentiation factor 88 (MyD88) or IL-1 receptor-associated kinase (IRAK)-1 triggered IFN- promoter activation. IRF-1 physically interacted with MyD88 and activation of mDC via TLR-9 induced IRF-1-dependent IFN- production paralleled by rapid transcriptional activation of IFN-stimulated genes. The NF-B-dependent production of pro-inflammatory cytokines, however, was not influenced by IRF-1. TLR-9 signaling through this pathway conferred cellular antiviral resistance while IRF-1-deficient mice displayed enhanced susceptibility to viral infection. These results demonstrate that TLR-9 activation of mDC and macrophages contributes to antiviral immunity via IRF-1. AU - Schmitz, F.* AU - Heit, A.* AU - Guggemoos, S. AU - Krug, A.* AU - Mages, J.* AU - Schiemann, M.* AU - Adler, H. AU - Drexler, I. AU - Haas, T.* AU - Lang, R.* AU - Wagner, H.* C1 - 5717 C2 - 24381 SP - 315-327 TI - Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN- production in myeloid dendritic cells. JO - Eur. J. Immunol. VL - 37 IS - 2 PB - Wiley-VCH PY - 2007 SN - 0014-2980 ER - TY - JOUR AU - Huster, K.M. AU - Koffler, M.* AU - Stemberger, C.* AU - Schiemann, M. AU - Wagner, H.* AU - Busch, D.H. C1 - 3587 C2 - 24019 SP - 1453-1464 TI - Undirectional development of CD8⁺ central memory T cells into protective Listeria-specific effector memory T cells. JO - Eur. J. Immunol. VL - 36 PB - Wiley-VCH PY - 2006 SN - 0014-2980 ER - TY - JOUR AU - Nera, K.-P.* AU - Alinikula, J.* AU - Terho, P.* AU - Narvi, E.* AU - Törnquist, K.* AU - Kurosaki, T.* AU - Buerstedde, J.-M. AU - Lassila, O.* C1 - 1375 C2 - 24146 SP - 516-525 TI - Ikaros has a crucial role in regulation of B cell receptor signaling. JO - Eur. J. Immunol. VL - 36 PB - Wiley-VCH PY - 2006 SN - 0014-2980 ER - TY - JOUR AU - Sommermeyer, D.* AU - Neudorfer, J.* AU - Weinhold, M.* AU - Leisegang, M.* AU - Engels, B.* AU - Nößner, E. AU - Heemskerk, M.H.* AU - Charo, J.* AU - Schendel, D.J. AU - Blankenstein, T.* AU - Bernhard, H. AU - Uckert, W.* C1 - 2440 C2 - 24024 SP - 3052-3059 TI - Designer T cells by T cell receptor replacement. JO - Eur. J. Immunol. VL - 36 IS - 11 PB - Wiley-VCH PY - 2006 SN - 0014-2980 ER - TY - JOUR AB - Recent evidence suggests that the functional status of T cells activated independently from their TCR differs substantially from classical MHC-restricted T cells. Here, we show that TCR-independent, short-term stimulation via the common gamma-chain of the IL-2/IL-15 receptor induces non-MHC-restricted cytotoxicity and sustained cytokine secretion in purified CD4+ or CD8+ T cells. NK-like cytotoxicity is directed against MHC class I-negative targets and can be inhibited by classical and non-classical HLA class I molecules. Known inhibitory receptors, such as CD85j (ILT2) and leukocyte-associated Ig-like receptor-1, are not responsible for this HLA-mediated inhibition. NK-like cytotoxicity can be costimulated by NKG2D (CD314) triggering, but 2B4 (CD244) and DNAM-1 (CD226) are not involved. NK-like T cells display an activated phenotype and secrete various cytokines, including IFN-gamma, TNF-alpha, IL-5, IL-13 and MIP-1beta. Under normal conditions, HLA class I-mediated inhibition may function as a safety mechanism to prevent unbalanced cytokine production and effector killing mechanisms by T cells that were activated independently from their TCR. Non-MHC-restricted activity represents a functional status rather than a property of distinct T cell subpopulations. Thus, cytokine-induced, non-MHC-restricted T cells may be relevant in immune responses against tumors showing aberrant MHC expression through their capacities of cytokine production and direct tumor cell eradication. AU - von Geldern, M. AU - Simm, B. AU - Braun, M. AU - Weiß, E.H.* AU - Schendel, D.J. AU - Falk, C.S. C1 - 4777 C2 - 23976 SP - 2347-2358 TI - TCR-independent cytokine stimulation induces non-MHC-restricted T cell activity and is negatively regulated by HLA class I. JO - Eur. J. Immunol. VL - 36 IS - 9 PB - Wiley-VCH PY - 2006 SN - 0014-2980 ER - TY - JOUR AB - Tissue-selective homing is established during naive T cell activation by the tissue microenvironment and tissue-specific dendritic cells (DC). The factors driving induction and maintenance of T cell homing patterns are still largely unknown. Here we show that soluble factors produced during the interaction of T cells with CD11c + DC isolated from skin- or small intestine-associated tissues differentially modulate expression of the corresponding tissue-selective homing receptors (E-selectin ligands and α4β7 integrin/CCR9, respectively) on murine CD8 + T cells. Injection of tissue-specific DC via different routes induces T cells with homing receptors characteristic of the corresponding local tissue microenvironment, independent of the origin of the DC. These data indicate an important role for signals delivered in trans. Moreover, DC can reprogram the homing receptor expression on T cells previously polarized in vitro for homing to skin or small intestine. Importantly, skin-homing memory T cells stimulated directly ex vivo can also be reprogrammed by intestinal DC to a gut-homing phenotype. Our results show that tissue-selective homing receptor expression on effector and memory T cells is governed by inductive as well as suppressive signals from both DC and tissue microenvironments. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. AU - Dudda, J.C.* AU - Lembo, A* AU - Bachtanian, E* AU - Hühn, J.* AU - Siewert, C* AU - Hamann, A* AU - Kremmer, E. AU - Forster, R.* AU - Martin, S.F.* C1 - 438 C2 - 23022 SP - 1056-1065 TI - Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments. JO - Eur. J. Immunol. VL - 35 IS - 4 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - Immunoregulatory T cells of CD4+CD25+ phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4+CD25high regulatory T cells (Treg) to confer suppression of myelin-specific immune responses. Whereas Treg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4+CD25high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of Treg, suggesting that a defective immunoregulation of peripheral T cells mediated by CD4+CD25high T lymphocytes promotes CNS autoimmunity in MS. AU - Haas, J.* AU - Hug, A.* AU - Viehöver, A.* AU - Fritzsching, B.* AU - Falk, C.S. AU - Filser, A.* AU - Vetter, T.* AU - Milkova, L.* AU - Korporal, M.* AU - Fritz, B.* AU - Storch-Hagenlocher, B.* C1 - 2436 C2 - 23070 SP - 3343-3352 TI - Reduced suppressive effect of (CD4plus)CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. JO - Eur. J. Immunol. VL - 35 IS - 11 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - Adoptive immunotherapy with antigen-specific T cells has been successfully used to treat certain infectious diseases and cancers. Although more patients may profit from T cell therapy, its more frequent use is restricted by limitations in current T cell generation strategies. The most commonly applied peptide-based approaches rely on the knowledge of relevant epitopes. Therefore, T cells cannot be generated for diseases with unknown epitopes or for patients with unfavorable HLA types. We developed a peptide-based approach for HLA type-independent generation of specific T cells against various proteins. It is based on short-time stimulation with peptide libraries that cover most CD4+ and CD8+ T cell epitopes of given proteins. The procedure requires no prior knowledge of epitopes because libraries are synthesized solely on the basis of the protein's amino acid sequence. Stimulation is followed by immunomagnetic selection of activated IFN-γ-secreting cells and nonspecific expansion. To evaluate the protocol, we generated autologous T cells specific for a well-characterized antigen, the human cytomegalovirus phosphoprotein 65 (pp65). Generated T cell lines consisted of pp65-specific CD4+ and CD8+ lymphocytes that displayed antigen-specific killing and proliferation. The protocol combines the biosafety of peptide-based approaches with HLA type independence and may help to advance adoptive immunotherapy in the future. AU - Hammer, M.H.* AU - Meyer, S.* AU - Brestrich, G.* AU - Moosmann, A. AU - Kern, F.* AU - Tesfa, L.* AU - Babel, N.* AU - Mittenzweig, A.* AU - Rooney, C.M.* AU - Hammerschmidt, W. AU - Volk, H.-D.* C1 - 3776 C2 - 22980 SP - 2250-2258 TI - HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy. JO - Eur. J. Immunol. VL - 35 IS - 7 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - Activation-induced cytidine deaminase (AID) plays a key role in the induction of somatic hypermutation and class switching at the immunoglobulin loci of B lymphocytes. AID overexpression can induce a mutator phenotype in lymphoid and nonlymphoid cell lines, suggesting that AID by itself is sufficient to trigger hypermutation and class switching. AID expression in vivo is considered to be restricted to germinal center B lymphocytes, yet AID expression is also seen in many B cell lymphomas, hinting at a potential role for the development of these malignancies. We used a GFP-based reversion assay to efficiently evaluate the activation of mutator phenotypes. As expected, AID overexpression in the human Burkitt lymphoma cell line BL70 caused hypermutation. Surprisingly, AID overexpression in the human pre-B cell line Nalm-6 failed to induce a detectable mutator phenotype, indicating that Nalm-6 cells are probably lacking an essential factor(s) to confer AID-induced mutagenesis. This finding supports the concept that AID overexpression by itself must not automatically lead to the onset of a mutator phenotype. In addition, treating Nalm-6 transfectants with thymidine, a potential mutagenic drug, caused profound mutation rates on the GFP transgene. Thus, the GFP-based mutation assay might prove a powerful tool to study protein- and chemical-induced mutator phenotypes in cell lines. AU - Rückerl, F. AU - Bachl, J. C1 - 3352 C2 - 22376 SP - 290-298 TI - Activation-induced cytidine deaminase fails to induce a mutator phenotype in the human pre-B cell line Nalm-6. JO - Eur. J. Immunol. VL - 35 IS - 1 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - Efficient protocols to generate cytomegalovirus (CMV)-specific T cells are required for adoptive immunotherapy. Recombinant Epstein-Barr virus (EBV) vectors called mini-EBV can be used to establish permanent B cell lines in a single step, which present the CMV antigen pp65 in a constitutive manner. These B cell lines, coined pp65 mini-LCL, were successfully used to reactivate and expand CMV-specific cytotoxic T cells. Here we evaluate this pp65 mini-EBV system in closer detail, focusing on (1) the quantification of T cells with specific effector function and (2) the identification of CMV-specific CD4+ helper T cells. The co-expansion of various functional CMV epitope specificities was demonstrated by IFN-γ enzyme-linked immunospot assay (ELISPOT) assays and HLA-peptide tetramer staining. Single-cell cloning resulted in both CD4+ and CD8+ T cell clones, the majority of which was CMV specific. Thus, mini-LCL present the pp65 antigen on HLA class I and II, mobilizing both arms of the T cell response. Using a peptide library covering the pp65 sequence for further analysis of T cell clones, we identified new pp65 CD8+ and CD4+ T cell epitopes. AU - Wiesner, M. AU - Zentz, C. AU - Hammer, M.H.* AU - Cobbold, M.* AU - Kern, F.* AU - Kolb, H.-J. AU - Hammerschmidt, W. AU - Zeidler, R.* AU - Moosmann, A. C1 - 2305 C2 - 22936 SP - 2110-2121 TI - Selection of CMC-specific CD8⁺ and CD4⁺ T cells by mini-EBV-transformed B cell lines. JO - Eur. J. Immunol. VL - 35 IS - 7 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - It has been speculated that somatic hypermutation of rearranged immunoglobulin variable (V) region genes does not only take place in the germinal center (GC) microenvironment, but also in the marginal zone (MZ) of the spleen, and that human peripheral blood IgM-positive B cells with somatically mutated V region genes may derive from mutating MZ B cells. As somatic hypermutation is strictly dependent on the enzyme activation-induced cytidine deaminase (AID), we used an AID-specific monoclonal antibody that is suitable for immunohistochemical staining to analyze human splenic MZ cells for AID expression. Analysis of tissue sections from 29 spleens revealed only very rare MZ cells (approx. 0.05%) showing AID staining, whereas in 25 of the spleen samples strong AID staining of GC B cells was observed. Thus, there are virtually no AID-expressing MZ B cells, indicating that somatic hypermutation does not take place at a significant level in the MZ. Consequently, it appears unlikely that the somatically mutated IgM B cells are generated in the splenic MZ. Moreover, the lack of AID-positive MZ B cells questions the recent speculation that B cell chronic lymphocytic leukemias with mutated V genes are derived from mutating MZ B cells. AU - Willenbrock, K.* AU - Jungnickel, B. AU - Hansmann, M.-L.* AU - Kuppers, R.* C1 - 3286 C2 - 23080 SP - 3002-3007 TI - Human Splenic marginal zone B cells lack expression of activation-induced cytidine deaminase. JO - Eur. J. Immunol. VL - 35 IS - 10 PB - Wiley-VCH PY - 2005 SN - 0014-2980 ER - TY - JOUR AB - The death of individual cells is a frequent and physiological event in the mammalian immune system and most often occurs by apoptosis. It is becoming increasingly clear that cell death is alsoinduced during bacterial infections. Here we report that, in addition to the apoptotic form already established, a necrosis-like form of cell death is induced by pyogenic bacteria (Enterobacteriaceae, Pseudomonas, enterococci) in mouse macrophages. Necrosis could be separated from apoptosis as it did not require phagocytosis of bacteria and occurred when apoptosis was inhibited by caspase blockade or by Bcl-2. Furthermore, ligands that stimulate Toll-like receptors were also found to have the capacity to induce necrosis. Strikingly, this form of cell death was sufficient for the uptake of dead cells by either mouse bone marrow-derived DC or a cell line derived from DC, possibly by virtue of the externalization of phosphatidylserine. Since the loading with bacteria-carrying cells is likely to impact on DC function, this form of necrosis may have a previously unsuspected role in the development of an immune response. AU - Kirschnek, S.* AU - Scheffel, J.* AU - Heinzmann, U. AU - Häcker, G.* C1 - 2135 C2 - 22129 SP - 1461-1471 TI - Necrosis-like cell death induced by bacteria in mouse macrophages. JO - Eur. J. Immunol. VL - 34 IS - 5 PB - Wiley-VCH PY - 2004 SN - 0014-2980 ER - TY - JOUR AB - Experimental and human organ transplant studies suggest an important role for chemokine (C-C-motif) receptor-5 (CCR5) in the development of acute and chronic allograft rejection. Because early transplant damage can predispose allografts to chronic dysfunction, we sought to identify potential pathophysiologic mechanisms leading to allograft damage by using wild-type and Ccr5-deficient mice as recipients of fully MHC-mismatched heart and carotid-artery allografts. Gene expression in rejecting heart allografts was analyzed 2 and 6 days after transplantation using Affymetrix GeneChips. Microarray analysis led to identification of four metalloproteinase genes [matrix metalloproteinase (Mmp)3, Mmp12, Mmp13 and a disintegrin and metalloprotease domain (Adam)8] with significantly diminished intragraft mRNA expression in Ccr5-deficient mice at day 6. Accordingly, allografts from Ccr5-deficient mice showed less tissue remodeling and hence better preservation of the myocardial architecture compared with allografts from wild-type recipients. Moreover, survival of cardiac allografts was significantly increased in Ccr5-deficient mice. Carotid artery allografts from Ccr5-deficient recipients showed better tissue preservation, and significant reduction of neointima formation and CD3+ T cell infiltration. Ccr5 appears to play an important role in transplant-associated arteriosclerosis that may involve metalloproteinase-mediated vessel wall remodeling. We conclude that early tissue remodeling may be a critical feature in the predisposition of allografts to the development of chronic dysfunction. AU - Luckow, B.* AU - Wurst, W. C1 - 4069 C2 - 22416 SP - 2568-2578 TI - Reduced intragraft mRNA expression of matrix metalloproteinases Mmp3, Mmp12, Mmp13 and Adam8 and diminished transplant arteriosclerosis in Ccr5-deficient mice. JO - Eur. J. Immunol. VL - 34 IS - 9 PB - Wiley-VCH PY - 2004 SN - 0014-2980 ER - TY - JOUR AB - The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein regularly expressed in EBV-associated malignancies. Immune recognition of EBNA1 by CD8+ T cells is prevented by an internal glycine-alanine repeat (GAr) which blocks proteasomal degradation. To test whether EBV-infected cells could be recognized by T helper cells, human CD4+ T cell clones specific for EBNA1 were isolated from latently EBV-infected individuals. These T cells, however, failed to recognize EBV-positive target cells. To investigate whether endogenous presentation of EBNA1 epitopes on MHC class II was prevented by the GAr domain, a mutant EBV strain with an EBNA1 lacking the GAr (EBNA1ΔGA) was generated and used to establish an Epstein-Barr virus-immortalized lymphoblastoid B cell line (LCL). The EBNA1ΔGA LCL were not recognized by the EBNA1-specific T cell clones either, indicating that the GAr domain does not mediate this effect. Immune recognition could be restored by overexpression of EBNA1, for which at least 60-fold higher levels of both EBNA1 or EBNA1ΔGAr protein were required. These results demonstrate that EBNA1 evades direct recognition by CD4+ T helper cells, since its steady state level is below the threshold required for efficient presentation on MHC class II. These findings have important implications for the design of immunotherapeutic approaches to target EBV-positive malignancies. AU - Mautner, J. AU - Pich, D. AU - Nimmerjahn, F. AU - Milosevic, S.* AU - Adhikary, D. AU - Christoph, H. AU - Witter, K.* AU - Bornkamm, G.W. AU - Hammerschmidt, W. AU - Behrends, U. C1 - 4706 C2 - 22092 SP - 2500-2509 TI - Epstein-Barr virus nuclear antigen 1 evades direct immune recognition by CD4+ T helper cells. JO - Eur. J. Immunol. VL - 34 IS - 9 PB - Wiley-VCH PY - 2004 SN - 0014-2980 ER - TY - JOUR AB - Secondary diversification of immunoglobulin (Ig) genes occurs through somatic hypermutation (SHM) in B cells of the germinal center (GC). The GC reaction is associated with a high frequency of DNA double-strand breaks (DSB) in the hypermutation domain of Ig genes. Homologous recombination (HR) is a prominent DSB repair pathway. Among the proteins involved in HR are the Rad-54 paralogues, Rad54 and Rad54B. To investigate whether Rad54/Rad54B-mediated HR is involved in SHM, we determined the ratio of mutated versus non-mutated Vlambda PCR products from memory (IgM-, IgD-, Vlambda1+) and GC (PNA(high), Vlambda1+) B cells, the mutation load, the mutation frequency, the base exchange pattern and the distribution of somatic mutations along the rearranged Vlambda light chain (VlambdaLC) genes. All these parameters of SHM were unaltered in memory and GC B cells lacking one or both Rad54 paralogues. Thus, our data indicate that Rad54 and Rad54B-mediated HR is not essential for SHM. In addition, the finding that the ablation of RAD51 paralogues causes an increase in SHM argues against a direct involvement of HR in promoting SHM. AU - Bross, L.* AU - Wesoly, J.* AU - Buerstedde, J.M. AU - Kanaar, R.* AU - Jacobs, H.* C1 - 5383 C2 - 21714 CY - Weinheim SP - 352-357 TI - Somatic hypermutation does not require Rad54 and Rad54B-mediated homologous recombination. JO - Eur. J. Immunol. VL - 33 IS - 2 PB - Wiley-VCH Verl. PY - 2003 SN - 0014-2980 ER - TY - JOUR AB - Biochemical and functional studies have demonstrated major histocompatibility complex (MHC) class II-restricted presentation of peptides derived from cytosolic proteins, but the underlying processing and presentation pathways have remained elusive. Here we show that endogenous presentation of an epitope derived from the cytosolic protein neomycin phosphotransferase II (NeoR) on MHC classII is mediated by autophagy. This presentation pathway involves the sequestration of NeoR into autophagosomes, and subsequent delivery into the lytic compartment. These results identify endosomes/lysosomes as the processing compartment for cytosolic antigens and furthermore link endogenous antigen presentation on MHC class II with the process of cellular protein turnover by autophagy. AU - Nimmerjahn, F. AU - Milosevic, S. AU - Behrends, U. AU - Jaffee, E.M.* AU - Pardoll, D.M.* AU - Bornkamm, G.W. AU - Mautner, J. C1 - 22248 C2 - 21008 SP - 1250-1259 TI - Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. JO - Eur. J. Immunol. VL - 33 IS - 5 PB - Wiley-VCH PY - 2003 SN - 0014-2980 ER - TY - JOUR AB - Patients with hypereosinophilia frequently suffer from eosinophil-mediated damages of the heart, lungs, skin, and other organs, while some do not. The reason(s) for this difference is not known. We observed that eosinophils from most patients with hypereosinophilia express the α-chain of the IL-2 receptor (CD25), and that IL-2 enhances platelet-activating factor-stimulated release ofeosinophil cationic protein from CD25-expressing but not from CD25-negative eosinophils. Such a "priming" effect has previously been described for eosinophil hematopoietins. These data suggest thatpatients with increased eosinophil surface CD25 expression are at higher risk of eosinophil degranulation and subsequent tissue damage when IL-2 is present at inflammatory sites. AU - Simon, H.-U.* AU - Plötz, S.G. AU - Simon, D.* AU - Seitzer, U.* AU - Braathen, L.R.* AU - Menz, G.* AU - Straumann, A.* AU - Dummer, R.* AU - Levi-Schaffer, F.* C1 - 10190 C2 - 21766 SP - 834-839 TI - Interleukin-2 primes eosinophil degranulation in hypereosinophilia and Well's syndrome. JO - Eur. J. Immunol. VL - 33 IS - 4 PB - Wiley-VCH PY - 2003 SN - 0014-2980 ER - TY - JOUR AB - Chlamydia pneumoniae stimulates potently maturation of and cytokine secretion by bone marrow-derived dendritic cells (BMDDC). BMDDC responses depend mainly on Toll-like receptor (TLR) 2 and to a minor extent on TLR4. We demonstrate here using C. pneumoniae in an infectious model with the replication-permissive epithelial cell line HEp2 that HSP60 is produced in substantial amounts in chlamydial inclusions during infection. Electron microscopy of chlamydial inclusions revealed that HSP60 was mainly associated with reticulate bodies, but was also located in between the different chlamydial developmental forms. Supernatants of permissive HEp2 cells infected with C. pneumoniae contained soluble chlamydial HSP60 as demonstrated by Western blotting and were able to stimulate BMDDC of wild-type mice. The stimulatory capacity of culture supernatants correlated with the presence of chlamydial HSP60. In contrast, BMDDC from TLR4-mutant mice crossed to TLR2-deficient mice were not stimulated by the culture supernatant, indicating that chlamydial HSP60 but not cytokines, possibly secreted by infected HEp2 cells, are responsible for the observed stimulation of BMDDC. Purified recombinant HSP60 from C. pneumoniae stimulated BMDDC in a TLR2- and TLR4-dependent fashion similar to the whole microorganism. In summary, these data suggest chlamydial HSP60 as an important mediator of inflammatory responses during infection with C. pneumoniae. AU - da Costa, C.P.* AU - Kirschning, C.J.* AU - Busch, D.H.* AU - Dürr, S.* AU - Jennen, L. AU - Heinzmann, U. AU - Prebeck, S.* AU - Wagner, H.M.* AU - Miethke, T.* C1 - 33112 C2 - 20528 SP - 2460-2470 TI - Role of chlamydial heat shock protein 60 in the stimulation of innate immune cells by Chlamydia pneumoniae. JO - Eur. J. Immunol. VL - 32 IS - 9 PY - 2002 SN - 0014-2980 ER - TY - JOUR AB - In human peripheral blood the classical CD14++DR+ monocytes and the pro-inflammatory CD14+CD16+DR++ monocytes can be distinguished. In erysipelas we found strongly increased numbers of CD14+CD16+ monocytes on the day of diagnosis (day 1) in 11 patients with an average of 150.5±76.0 cells/μl, while 1 patient had low levels (35 cells/μl, control donors 48.8±19.8 cells/μl). The classical monocytes were only moderately elevated in the erysipelas patients (factor 1.7 as compared to controls). Patients exhibited increased body temperature, erythrocyte sedimentation rate and increased serum levels for C-reactive protein (CRP), IL-6 and macrophage-colony-stimulating factor. Among these, body temperature and CRP showed a significant correlation to the numbers of CD14+CD16+ monocytes. In 4 of 4 patients with high levels of CD14+CD16+ monocytes, these levels returned to that seen in controls by day 5 of antibiotic therapy. Determination of intracellular TNF was performed by three-color immunofluorescence and flow cytometry after ex vivo stimulation withlipoteichoic acid, a typical constituent of streptococci. Here, patient CD14+DR++ pro-inflammatory monocytes showed a twofold lower level of intracellular TNF. By contrast, expression of TNF was unaltered in the classical CD14++ monocytes. These data show that in erysipelas the pro-inflammatory CD14+CD16+DR++ monocytes are substantially expanded and selectively tolerant to stimulation by streptococcal products.   AU - Horelt, A.* AU - Belge, K.-U.* AU - Steppich, B.* AU - Prinz, J.* AU - Ziegler-Heitbrock, L. C1 - 10188 C2 - 20677 SP - 1319-1327 TI - The CD14+CD16+ monocytes in erysipelas are expandend and show reduced cytokine production. JO - Eur. J. Immunol. VL - 32 IS - 5 PB - Wiley-VCH PY - 2002 SN - 0014-2980 ER - TY - JOUR AB - Members of the heat shock protein (hsp70) family are either constitutively expressed (hsc70) or can be induced by hyperthermic stress (hsp70). Recombinant hsp70 (rhsp70) stimulates cytokine production from monocytes and enhances NK cell proliferation and cytotoxicity. Here we demonstrate that rhsp70 binds to immature dendritic cells (DC) derived from monocyte precursors and induces theirmaturation as evidenced by an increase in CD40, CD86 and CD83 expression. Immature DC stimulated to mature with rhsp70 show an enhanced ability to present tyrosinase peptide to specific CTL. MatureDC did not bind rhsp70, suggesting a down-regulation in the expression of its receptor. When rhsp70 was added to monocyte precursors at the same time as GM-CSF and IL-4 it reduced the differentiation of monocytes into DC as shown by a decrease in the level of CD40, CD83, CD86 and HLA-DR expression and an increase in CD14 expression. The constitutively expressed hsc70 had neither a stimulatoryeffect on the maturation of immature DC nor did it reduce the differentiation of monocytes into DC. These findings demonstrate the specific ability of rhsp70 to induce the maturation of immature DC. Therefore rhsp70 may be useful for its adjuvant like properties in DC based immunotherapy of certain tumors. AU - Kuppner, M.C.* AU - Gastpar, R. AU - Gelwer, S.* AU - Nössner, E. AU - Ochmann, O.* AU - Scharner, A.* AU - Issels, R.D. C1 - 22183 C2 - 20887 SP - 1602-1609 TI - The role of heat shock protein (hsp70) in dendritic cell maturation : Hsp70 induced the maturation of immature dendritic cells but reduces DC differentation from monocyte precursors. JO - Eur. J. Immunol. VL - 31 IS - 5 PB - Wiley-VCH PY - 2001 SN - 0014-2980 ER - TY - JOUR AB - The chemokine RANTES is produced by a variety of tissues, including cells of the monocyte/macrophage lineage. RANTES expression is rapidly and transiently up-regulated in primary monocytes and the monocytic cell line Mono Mac 6 in response to stimulation by the bacterial product lipopolysaccharide (LPS). Transient transfection of Mono Mac 6 cells with RANTES reporter-promoter deletion constructs, in conjunction with DNase I footprinting and heterologous reporter gene assays, allowed identification of an LPS-responsive region within the RANTES promoter. Electrophoretic mobility shift assays (EMSA), methylation interference and EMSA supershift experiments were used to characterize sequences and transcription factors responsible for this LPS inducibility. The region, termed RANTES site G [R(G)], contains consensus sites for Ets and CRE/AP-1-like elements. Site-directed mutagenesis of the Ets site resulted in a loss of only 15 % of promoter activity, while mutation of the CRE/AP-1 site led to a loss of 40 % of LPS-induced promoter activity. The Ets site constitutively binds the Ets family member PU.1. LPS stimulation leads to an induction of ATF-3 and JunD factor binding to the CRE/AP-1 site. Thus, LPS induction of RANTES transcription is mediated, in part, through the activation and selective binding of ATF and Jun nuclear factors to the R(G) promoter module. AU - Boehlk, S.* AU - Fessele, S.* AU - Mojaat, A.* AU - Miyamoto, N.G.* AU - Werner, T. AU - Nelson, E.L.* AU - Schlöndorff, D.* AU - Nelson, P.J.* C1 - 22711 C2 - 19730 SP - 1102-12 TI - ATF and Jun transcription factors, acting through an Ets/CRE promoter module, mediate lipopolysaccharide inducibility of the chemokine RANTES in monocytic Mono Mac 6 cells. JO - Eur. J. Immunol. VL - 30 IS - 4 PB - Wiley-VCH PY - 2000 SN - 0014-2980 ER - TY - JOUR AU - Lang, R.* AU - Hültner, L. AU - Lipford, G.B.* AU - Wagner, H.* AU - Heeg, K.* C1 - 21148 C2 - 19189 SP - 3496-3506 TI - Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of murine bone marrow cells. JO - Eur. J. Immunol. VL - 29 PY - 1999 SN - 0014-2980 ER - TY - JOUR AB - When naive T lymphocytes are activated and differentiate into memory/effector cells, they down-regulate receptors for constitutive chemokines such as CXCR4 and CCR7 and acquire receptors for inflammatory chemokines such as CCR3, CCR5 and CXCR3, depending on the Th1/Th2 polarization. This switch in chemokine receptor usage leads to the acquisition of the capacity to migrate into inflamed tissues. Using RNase protection assays, staining with specific antibodies, and response to recombinant chemokines, we now show that following TCR stimulation, memory/effector T cells undergo a further and transient switch in receptor expression. CCR1, CCR2, CCR3, CCR5, CCR6 and CXCR3 are down-regulated within 6 h, while CCR7, CCR4, CCR8 and CXCR5 are up-regulated for 2 to 3 days. Up-regulation of CCR7 following TCR stimulation was observed also among resting peripheral blood T cells and required neither co-stimulation nor exogenous IL-2. On the other hand IL-2 down-regulated CXCR5, up-regulated CCR8 and facilitated the recovery of CCR3 and CCR5. Upon TCR stimulation, Th1 and Th2 cells produced comparable sets of chemokines, including RANTES, macrophage inflammatory protein-1beta, I-309, IL-8 and macrophage-derived chemokine, which may modulate surface chemokine receptors and contribute to cell recruitment at sites of antigenic recognition. Altogether these results show that following TCR stimulation effector/memory T cells transiently acquire responsiveness to constitutive chemokines. As a result, T cells that are activated in tissues may either recirculate to draining lymph nodes or migrate to nearby sites of organized ectopic lymphoid tissues. AU - Sallusto, F.* AU - Kremmer, E. AU - Palermo, B.* AU - Hoy, A.* AU - Ponath, P.* AU - Qin, S.* AU - Forster, R.* AU - Lipp, M.* AU - Lanzaveccia, A.* C1 - 21063 C2 - 19093 SP - 2037-2045 TI - Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. JO - Eur. J. Immunol. VL - 29 IS - 6 PY - 1999 SN - 0014-2980 ER - TY - JOUR AB - Gene targeting in hybridoma cells provides a tool for generating chimeric antibodies with great ease and at high yield. We present an evaluation of integration vectors for the chimerization of the immunoglobulin heavy chain locus which are universally applicable to hybridomas of different isotypes and mouse strains. There are three problems arising with vector integration: (i) the frequent persistence of the parental isotype; (ii) an isotype-dependent aberrant replacement-like recombination giving rise to antibodies devoid of the CH1 domain; and (iii) secondary recombinations leading to excision of the integrated sequence. To overcome these problems, we have systematically evaluated the consequences of extending the vector flank. Although the homology length clearly determines the recombination frequency, this effect is counteracted by the secondary recombination, which also correlates to the homology length. In contrast, the truncating recombination events are not dependent on the homology length and never lead to re-excision of the construct. To take advantage of the increased genetic stability obtained with short flanks, we constructed an enrichment vector which yields high recombination efficiencies despite using a short flanking sequence. In addition, irradiation of the cells enhanced homologous recombination. The problem of the co-production of two isotypes was overcome by a two-step targeting reaction. AU - Kardinal, C. AU - Hooijberg, E.* AU - Lang, P. AU - Zeidler, R. AU - Mocikat, R. C1 - 27614 C2 - 32767 SP - 792-797 TI - Integration vectors for antibody chimerization by homologous recombination in hybridoma cells. JO - Eur. J. Immunol. VL - 25 IS - 3 PY - 1995 SN - 0014-2980 ER - TY - JOUR AB - The immunoglobulin heavy chain 3' enhancer may be a novel type of a transcriptional regulation element in as much as its function is position dependent. We show that there are interactions between the mu intron and 3' enhancer which are differentially regulated depending on the distance between the two elements. Thus, a transcriptional repression is exerted by the 3' enhancer when juxtaposed to the intron enhancer. Whereas no or only modest synergism between the immunoglobulin mu intron and 3' enhancer has been reported to date, we show here that the stimulatory effect is substantially increased by extending the distance between the two enhancers. In our stable expression system, the mu intron enhancer insulated the test gene from neighboring chromatin. AU - Mocikat, R. AU - Kardinal, C. AU - Klobeck, H.-G.* C1 - 39842 C2 - 0 SP - 3195-3198 TI - Differential interactions between the immunoglobulin heavy chain mu intron and 3' enhancer. JO - Eur. J. Immunol. VL - 25 IS - 11 PY - 1995 SN - 0014-2980 ER - TY - JOUR AB - Formation of anti-antibodies (anti-Ab) is known to counteract immunotherapy with anti-T cell antibodies. Our previously described immunological approach prevented anti-Ab with the consequence of prolonged survival of fully mismatched skin grafts in C57BL/6 mice. These mice were treated with a single priming injection of a monoclonal anti-T cell Ab followed by repeated injections of anti-T cell mAb differing in species origin from the priming mAb. We now show prolonged tolerance to discordant xenogeneic, to bispecific, and even to polyclonal Ab, and demonstrate that the underlying immunosuppressive principle is due to a difference in heavy chain constant region between first and second antibodies, independent of whether or not they share the same idiotype. To examine this phenomenon, a panel of mAb was generated which share the same mouse anti-Thy-1.2 idiotype, but carry a human IgG1(T23), IgG3(T212C8), or mouse IgG2a(MmT1) constant heavy chain region. We found that sequential injection of MmT1 and T23 according to the above treatment schedule induced huIgG1 isotype-specific tolerance to T23, which was similar to that seen when using a primary mAb (MmT5) that was, instead, fully mismatched with T23 in both idiotype and constant region. Thus, differences of idiotype between primary and booster Ab were inconsequential for their ability to inhibit anti-Ab formation. This novel form of induced specific tolerance to anti-T cell Ig survived graft rejection and was still evident 230 days after termination of the T cell depletion protocol. Taken together, these results demonstrate that rechallenge with Fc region-mismatched Ab opens an immunological window that allows for induction of tolerance to immunogenic anti-T cell Ab and prolonged immunosuppression. AU - Thierfelder, S. AU - Mocikat, R. AU - Mysliwietz, J. AU - Lindhofer, H.G. AU - Kremmer, E. C1 - 39948 C2 - 0 SP - 2242-2246 TI - Immunosuppression by Fc region-mismatched anti-T cell antibody treatment. JO - Eur. J. Immunol. VL - 25 IS - 8 PY - 1995 SN - 0014-2980 ER - TY - JOUR AB - Inhibitory anti-antibodies induced in patients by xenogeneic or even by humanized anti-T cell antibodies remain an unresolved problem. Mice also produce anti-antibodies following injection of xeno- or allogeneic anti-T cell antibodies. Here we report a principle based on sequentially applied anti-T cell antibodies generated in different species, which results in suppressed anti-antibody formation and prolonged immunosuppression. Thus, a single priming injection in mice of mouse (MmT1 or MmT5 differing by idiotype only) or of rat (RmT1) anti-mouse Thy-1 monoclonal antibodies (mAb) or of rat anti-mouse L3T4 + Ly-2 (RmCD4 + CD8) mAb suppressed anti-antibody formation against subsequent booster injections of one of the above antibodies, provided that they differed in species origin from the priming antibody. Correspondingly, a sixfold and longer prolongation of 50% survival of fully mismatched skin grafts was observed. Less or no anti-antibody suppression and little prolongation of graft survival was obtained if the 'first' and the 'second' (and following) antibody injections were of the same species, differing by iso- or idiotype only. Finally, the suppressive principle did not manifest itself at all if the initial antibody injection included both the first and second antibody. These findings are discussed with reference to earlier studies on hapten/carrier effects as well as on immunosuppression attributed to 'non-depleting' rat anti-CD4/CD8 T cell antibodies. AU - Mysliwietz, J. AU - Thierfelder, S. AU - Mocikat, R. AU - Kremmer, E. C1 - 33937 C2 - 0 SP - 2323-2328 TI - Immunological approach to inhibit formation of anti-antibodies to allo- and xenogeneic anti-T cell immunoglobulin. JO - Eur. J. Immunol. VL - 24 IS - 10 PY - 1994 SN - 0014-2980 ER - TY - JOUR AB - Humanization of immunosuppressive anti-T cell monoclonal antibodies (mAb) raises the question as to how completely it helps to avoid formation of neutralizing anti-antibodies (anti-Ab) in patients. To get more information on intra-species sensitization against anti-T cell mAb, we produced two immunosuppressive mouse IgG2a anti-mouse Thy-1.2 mAb (MmT1 and MmT5) in AKR/J mice and measured the potential of MmT1 to elicit inhibitory anti-Ab in AKR/J (H-2k), C57BL/6 (H-2b), congenic B10.BR (H-2k) and DBA/2 (H-2d) mice. After one injection once weekly for 4 weeks of 5 micrograms MmT1 (200 micrograms/kg) in C57BL/6 mice, without the use of any adjuvants, high concentrations of anti-Ab directed against MmT1 (300 micrograms/ml) and MmT5 (100 micrograms/ml) were measured by enzyme-linked immunosorbent assay. Similar concentrations of anti-Ab were found in immunized DBA/2 and less in B10.BR mice. No syngeneic anti-Ab could be produced in AKR/J. From the C57BL/6 mice, we raised anti-MmT1+, MmT5- idiotype (IDIO1) and anti-MmT1+, MmT5+ allotype (ALLO1) mAb. An in vivo test system was adapted to measure the inhibitory effects of circulating poly- or monoclonal anti-Ab. It revealed a reduction of in vivo depletion capacity not only of the sensitizing mAb (MmT1), but also of another anti-Thy-1.2 mAb (MmT5), with identical allotype but different idiotype. From this we conclude that intra-species immunization following injection of anti-T cell mAb can produce high titer inhibitory anti-idiotype and anti-allotype antibodies. Implications for hyperchimeric or fully human anti-T cell mAb are discussed. AU - Kremmer, E. AU - Mysliwietz, J. AU - Lederer, R. AU - Thierfelder, S. C1 - 20351 C2 - 13542 SP - 1017-1022 TI - Murine Anti-Mouse T Cell Monoclonal Antibodies Elicit anti-antibodies in Mice: Intraspecies Immunization Model for Estimating Potential Patient Sensitization Against humanized anti-T cell Antibodies. JO - Eur. J. Immunol. VL - 23 IS - 5 PY - 1993 SN - 0014-2980 ER - TY - JOUR AB - Humanization of immunosuppressive anti-T cell monoclonal antibodies (mAb) raises the question as to how completely it helps to avoid formation of neutralizing anti-antibodies (anti-Ab) in patients. To get more information on intra-species sensitization against anti-T cell mAb, we produced two immunosuppressive mouse IgG2a anti-mouse Thy-1.2 mAb (MmT1 and MmT5) in AKR/J mice and measured the potential of MmT1 to elicit inhibitory anti-Ab in AKR/J (H-2(k)), C57BL/6 (H-2b), congenic B10.BR (H-2(k)) and DBA/2 (H-2(d)) mice. After one injection once weekly for 4 weeks of 5μg MmT1 (200μg/kg) in C57BL/6 mice, without the use of any adjuvants, high concentrations of anti-Ab directed against MmT1 (300 μg/ml) and MmT5 (100 μg/ml) were measured by enzyme-linked immunosorbent assay. Similar concentrations of anti-Ab were found in immunized DBA/2 and less in B10.BR mice. No syngeneic anti-Ab could be produced in AKR/J. From the C57BL/6 mice, we raised anti-MmT1+, MmT5- idiotype (IDI01) and anti-MmT1+, MmT5+ allotype (ALLO1) mAb. An in vivo test system was adapted to measure the inhibitory effects of circulating poly- or monoclonal anti-Ab. It revealed a reduction of in vivo depletion capacity not only of the sensitizing mAb (MmT1), but also of another anti-Thy-1.2 mAb (MmT5), with identical allotype but different idiotype. From this we conclude that intra-species immunization following injection of anti-T cell mAb can produce high titer inhibitory anti-idiotype and anti-allotype antibodies. Implications for hyperchimeric or fully human anti-T cell mAb are discussed. AU - Kremmer, E. AU - Mysliwietz, J. AU - Lederer, R. AU - Thierfelder, S.S. C1 - 40395 C2 - 40050 SP - 1017-1022 TI - Murine anti-mouse T cell monoclonal antibodies elicit anti-antibodies in mice: Intra-species immunization model for estimating potential patient sensitization against humanized anti-T cell antibodies. JO - Eur. J. Immunol. VL - 23 IS - 5 PY - 1993 SN - 0014-2980 ER - TY - JOUR AB - We analyzed the mechanism by which certain anti-Thy-1 monoclonal antibodies (mAb) activate T cells directly without additional stimuli. Using a panel of rat anti-Thy-1 antibodies which included more than 30 IgG2c mAb, we found that only the IgG2c isotype was able to induce a strong proliferative response in both resting T cells and a T cell lymphoma, suggesting that this form of T cell activation is isotype restricted and might be a consequence of a unique physico-chemical property of the IgG2c heavy chain. Results from surface distribution studies of Thy-1 molecules, following specific interactions with anti-Thy-1 antibodies of different isotypes, again showed that only IgG2c mAb formed Thy-1 aggregates of high valence on the surface of a T cell lymphoma, and such clustering always evoked a biological response. This led us to propose that IgG2c mAb have the inherent tendency to self-associate, probably through homophilic Fc-Fc contacts, and that this feature renders anti-Thy-1 mAb mitogenic. To prove this, we set up cross-inhibition studies with randomly selected mitogenic (IgG2c) and non-mitogenic (IgG2b) anti-Thy-1 mAb. The results clearly demonstrated that IgG2c antibodies enhance their own binding, analogous to the new form of antibody binding that was recently demonstrated between murine IgG3 mAb and a multivalent antigen. Confirmation of this was also provided by IgG2c-derived F(ab′)2 fragments, which were unable to cause proliferation. Furthermore, masking the Fc part of cell-bound IgG2c mAb with a monomeric and thus non-aggregating IgG-binding protein A-derived fragment cancelled their mitogenic ability. Finally, induction of T cell proliferation appeared to be independent of cross-linking via FcγR. The results support a model in which noncovalent intermolecular homophilic contacts of the Fc regions of the IgG2c isotype bring about effective aggregation of Thy-1 molecules, thereby stimulating the mitotic apparatus of the cell. AU - Kummer, U. AU - Haunschild, J. AU - Reisbach, G.* AU - Delecluse, H.J.* AU - Thierfelder, S.S. C1 - 40354 C2 - 40044 SP - 2649-2654 TI - Mitogenicity of anti-Thy-1 monoclonal antibodies attributable to an Fc-dependent mechanism. JO - Eur. J. Immunol. VL - 23 IS - 10 PY - 1993 SN - 0014-2980 ER - TY - JOUR AB - The successful engraftment in SCID mice of intraperitoneally (i.p.) injected human lymphocytes (hu-PBL-SCID) and the failure of intravenously injected peripheral blood lymphocytes (PBL) directed the present study to investigate the early events of donor cell proliferation in the peritoneal cavity. We found focal lymphocyte engraftment together with histio-monocytic interleukin (IL)-6+ cell phenotypes which must have been transferred with the human cell inoculum, which could explain certain immune functions observed in hu-PBL-SCID chimeras. Following i.p. injection of 108 PBL, human cells suspended in peritoneal fluid as well as those adherent to the serosal peritoneum and abdominal organs were investigated by immunocytology and immunohistology. Human cells were found to form foci consisting predominantly of proliferating human lymphoblastoid CD3+ cells, which were mostly activated HLA-DR+ CD8+ lymphocytes. Among the lymphoid cells larger epithelioid-like cells were found to belong to the monocytic series and to stain strongly with anti-HLA-DR and anti-CD11c antibodies. Some of these cells were also positive with anti-ICAM and anti-IL-6. Congenic as well as allogeneic mouse PBL, injected i.p. into SCID mice, temporarily produced analogous foci, which shifted later on to foci similar in appearance to milky spots. However, the human cell foci appeared less compact, more closely resembling in vitro-culture soft agar colonies. It is possible that cytokines in the human histio-monocytic cells of the foci may have a feeder effect on the human lymphocytes and be a prerequisite for proliferation of human PBL in SCID mice. The observed early HLA-DR activation of human lymphocytes in the peritoneal foci could reflect triggering of immune reactions like xenogeneic graft-versus-host reactions in the peritoneal site, where the human CD11c+ HLA-DR+ histio-monocytic cells may act as antigen-presenting cells. AU - Hoffmann-Fezer, G. AU - Kranz, B. AU - Gall, C. AU - Thierfelder, S. C1 - 20273 C2 - 13461 SP - 3161-3166 TI - Peritoneal Sanctuary for Human Lymphopoiesis in SCID Mice Injected with Human Peripheral Blood Lymphocytes of EBV-donors. JO - Eur. J. Immunol. VL - 22 IS - 12 PY - 1992 SN - 0014-2980 ER - TY - JOUR AB - Previously we proposed a concept for tumor immunotherapy in which two different bispecific antibody conjugates, an anti-target x anti-CD3 and an anti-target x anti-CD28 conjugate, induce the activation of resting humanTcells upon binding to the respective tumor target cells. After in vivo application of these reagents, this model of a "target cell-induced T cell activation" envisages the destruction of target cells by in situ activated T cells. Obviously however, for in vivo application, the use of Fc-free antibody fragments is mandatory to prevent binding of the conjugates to Fc receptor-positive cells which would lead to Fc-mediated T cell activation. Here we report a simplification of published procedures for the generation of bispecific Fab-hybrid fragments, univalent for each antigen. We demonstrate that an anti-target x anti-CDS/anti-target X antiCD28 combination of such hybrids, as well as an identical combination of covalently coupled F(ab′)2 fragments, mediate "target cell-induced Tcell activation" in an in vitro test system.Thus, these reagents may be capable of inducing an in situ activation of human T cells upon systemic in vivo application according to the concept outlined above. A trispecific conjugate with anti-target, anti-CD3-and anti-CD28 specificity appears to be unsuitable for this purpose because it activates resting T cells in soluble form without requiring immobilization through binding via its anti-target portion. AU - Jung, G.* AU - Freimann, U. AU - von Marschall, Z.* AU - Reisfeld, R.A.* AU - Wilmanns, W. C1 - 40741 C2 - 38036 SP - 2431-2435 TI - Target cell-induced T cell activation with bi- and trispecific antibody fragments. JO - Eur. J. Immunol. VL - 21 IS - 10 PY - 1991 SN - 0014-2980 ER - TY - JOUR AB - We have previously shown that certain bone marrow-derived mast cell (BMMC) lines proliferate in response to a mast cell growth-enhancing activity (MEA) that is distinct from interleukin (IL) 3 and IL 4. Here we provide evidence that MEA is identical with the recently cloned mouse T cell growth factor P40. The evidence is as follows: (a) recombinant P40 displayed all the biological activities ascribed to MEA: it supported the growth of MEA-sensitive BMMC lines, it induced IL 6 secretion by these cells, and it enhanced survival of primary mast cell cultures; (b) highly purified MEA stimulated the growth of P40-dependent cell lines; (c) a rabbit monospecific antiserum directed against P40 specifically inhibited the action of MEA on BMMC; (d) specific binding sites for P40 were detected on BMMC and (e) MEA competed with P40 for binding to P40-dependent T cells, indicating that the two molecules interact with the same receptor. These observations further extend the range of biological activities ascribed to P40 and warrant its proposed designation as IL9.20 AU - Hültner, L. AU - Druez, C. AU - Moeller, J. AU - Uyttenhove, C. AU - Schmitt, E. AU - Rüde, E. AU - Dörmer, P. AU - Snick, J. van C1 - 18399 C2 - 11601 SP - 1413-1416 TI - Mast cell growth enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). JO - Eur. J. Immunol. VL - 20 IS - 6 PY - 1990 SN - 0014-2980 ER - TY - JOUR AB - The current studies were designed to determine the relevance of T cell antigen density, besides antibody isotype, with regard to the success of antibody serotherapy. We compared the immunosuppressive effects of two rat IgG2b monoclonal anti-Thy-1 antibodies, RmT1 and 30-H12, with distinct binding sites in a graft-vs.-host disease (GVHD) model of fully H-2 and I-A region-mismatched bone marrow transplantation, making use of the difference in Thy-1.2 antigen density between homozygous (BALB/c) and heterozygous (BALB/c X AKR/J)F1 GVHD-promoting donor cells. Antibodies RmT1 (directed against a monomorphic determinant on mouse Thy-1) and 30-H12 (reactive with the Thy-1.2 allele-specific determinant) did not differ in their anti-GVHD activity with regard to Thy-1.2 homozygous grafts. However, in the region of a critical number of binding sites a small difference in the amounts of the two antibodies bound (about 8 X 10(3) IgG molecules/cell) obviously accounts for a great difference in anti-GVHD activity. This is shown in a two haplotype host-graft disparity between C57BL/6 recipients treated with either RmT1 or 30-H12 before challenging them with (BALB/c X AKR/J)F1 grafts, where the Thy-1.2 antigen concentration is approximately 50% compared to the density on BALB/c lymphocytes. Here, mAb 30-H12 loses its remarkable in vivo immunosuppressive quality, whereas RmT1 treatment protects mice against lethal GVHD. Binding sites were quantitated using a computerized approach for the analysis of data from ligand binding experiments of the respective mAb, RmT1 and 30-H12, coated to LN cells of BALB/c and F1 hybrid origin. Furthermore, the in vivo immunosuppressive activity of rat IgG2b antibodies directed against Thy-1 was found to correlate with their ability to generate stable antibody-C1q complexes on the cell surface of immunocompetent T cells. AU - Kummer, U. AU - Thierfelder, S. AU - Mysliwietz, J. C1 - 18302 C2 - 11133 SP - 107-112 TI - Antigen Density on Target Cells Determines the Immunosuppressive Potential of Rat IgG2b Monoclonal Antibodies. JO - Eur. J. Immunol. VL - 20 IS - 1 PY - 1990 SN - 0014-2980 ER - TY - JOUR AB - The current studies were designed to determine the relevance of T cell antigen density, besides antibody isotype, with regard to the success of antibody serotherapy. We compared the immunosuppressive effects of two rat IgG2b monoclonal anti-Thy-1 antibodies, RmT1 and 30-H12, with distinct binding sites in a graft-vs.-host disease (GVHD) model of fully H-2 and I-A region-mismatched bone marrow transplantation, making use of the difference in Thy-1.2 antigen density between homozygous (BALB/c) and heterozygous (BALB/c × AKR/J)F1 GVHD-promoting donor cells. Antibodies RmT1 (directed against a monomorphic determinant on mouse Thy-1) and 30-H12 (reactive with the Thy-1.2 allele-specific determinant) did not differ in their anti-GVHD activity with regard to Thy-1.2 homozygous grafts. However, in the region of a critical number of binding sites a small difference in the amounts of the two antibodies bound (about 8 × 103 IgG molecules/cell) obviously accounts for a great difference in anti-GVHD activity. This is shown in a two haplotype host-graft disparity between C57BL/6 recipients treated with either RmT1 or 30-H12 before challenging them with (BALB/c × AKR/J)F1 grafts, where the Thy-1.2 antigen concentration is approximately 50% compared to the density on BALB/c lymphocytes. Here, mAb 30-H12 loses its remarkable in vivo immunosuppressive quality, whereas RmT1 treatment protects mice against lethal GVHD. Binding sites were quantitated using a computerized approach for the analysis of data from ligand binding experiments of the respective mAb, RmT1 and 30-H12, coated to LN cells of BALB/c and F1 hybrid origin. Furthermore, the in vivo immunosuppressive activity of rat IgG2b antibodies directed against Thy-1 was found to correlate with their ability to generate stable antibody-C1q complexes on the cell surface of immunocompetent T cells. AU - Kummer, U. AU - Thierfelder, S.S. AU - Mysliwietz, J. C1 - 33995 C2 - 36399 SP - 107-112 TI - Antigen density on target cells determines the immunosuppressive potential of rat IgG2b monoclonal antibodies. JO - Eur. J. Immunol. VL - 20 IS - 1 PY - 1990 SN - 0014-2980 ER -