TY  - JOUR
AB  - CD4+ regulatory T (Treg) cells in tissues play crucial immunoregulatory and regenerative roles. Despite their importance, the epigenetics and differentiation of human tissue Treg cells are incompletely understood. Here, we performed genome-wide DNA methylation analysis of human Treg cells from skin and blood and integrated these data into a multiomic framework, including chromatin accessibility and gene expression. This analysis identified programs that governed the tissue adaptation of skin Treg cells. We found that subfamilies of transposable elements represented a major constituent of the hypomethylated landscape in tissue Treg cells. Based on T cell antigen receptor sequence and DNA hypomethylation homologies, our data indicate that blood CCR8+ Treg cells contain recirculating human skin Treg cells. Conversely, differences in chromatin accessibility and gene expression suggest a certain reversal of the tissue adaptation program during recirculation. Our findings provide insights into the biology of human tissue Treg cells, which may help harness these cells for therapeutic purposes.
AU  - Beumer, N.*
AU  - Imbusch, C.D.*
AU  - Kaufmann, T.*
AU  - Schmidleithner, L.*
AU  - Gütter, K.*
AU  - Stüve, P.*
AU  - Marchel, H.*
AU  - Weichenhan, D.*
AU  - Bähr, M.*
AU  - Ruhland, B.*
AU  - Marini, F.*
AU  - Sanderink, L.*
AU  - Ritter, U.*
AU  - Simon, M.*
AU  - Braband, K.L.*
AU  - Voss, M.M.*
AU  - Helbich, S.S.*
AU  - Mihoc, D.M.*
AU  - Hotz-Wagenblatt, A.*
AU  - Nassabi, H.*
AU  - Eigenberger, A.*
AU  - Prantl, L.*
AU  - Gebhard, C.*
AU  - Rehli, M.*
AU  - Strieder, N.*
AU  - Singh, K.
AU  - Schmidl, C.*
AU  - Plass, C.*
AU  - Huehn, J.*
AU  - Hehlgans, T.*
AU  - Polansky, J.K.*
AU  - Brors, B.*
AU  - Delacher, M.*
AU  - Feuerer, M.*
C1  - 75162
C2  - 57811
TI  - DNA hypomethylation traits define human regulatory T cells in cutaneous tissue and identify their blood recirculating counterparts.
JO  - Nat. Immunol.
PY  - 2025
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a VH1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml-1, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml-1, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.
AU  - Gieselmann, L.*
AU  - DeLaitsch, A.T.*
AU  - Rohde, M.*
AU  - Gruell, H.*
AU  - Kreer, C.*
AU  - Ercanoglu, M.S.*
AU  - Gristick, H.B.*
AU  - Schommers, P.*
AU  - Ahmadov, E.*
AU  - Radford, C.E.*
AU  - Mazzolini, A.*
AU  - Zhang, L.*
AU  - West, A.P.*
AU  - Worczinski, J.*
AU  - Momot, A.*
AU  - Reichwein, M.L.*
AU  - Knüfer, J.*
AU  - Stumpf, R.*
AU  - Mkhize, N.N.*
AU  - Kaldine, H.*
AU  - Bhebhe, S.*
AU  - Deshpande, S.*
AU  - Giovannoni, F.*
AU  - Stefanutti, E.*
AU  - Benigni, F.*
AU  - Havenar-Daughton, C.*
AU  - Corti, D.*
AU  - Kroidl, A.*
AU  - Adhikari, A.*
AU  - Nanfack, A.J.*
AU  - Ambada, G.E.*
AU  - Duerr, R.*
AU  - Maganga, L.*
AU  - William, W.*
AU  - Ntinginya, N.E.*
AU  - Wolf, T.*
AU  - Geldmacher, C.*
AU  - Hoelscher, M.
AU  - Lehmann, C.*
AU  - Moore, P.L.*
AU  - Mora, T.*
AU  - Walczak, A.M.*
AU  - Gilbert, P.B.*
AU  - Doria-Rose, N.A.*
AU  - Huang, Y.*
AU  - Bloom, J.D.*
AU  - Seaman, M.S.*
AU  - Bjorkman, P.J.*
AU  - Klein, F.*
C1  - 75721
C2  - 58125
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy.
JO  - Nat. Immunol.
PB  - Nature Portfolio
PY  - 2025
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
AU  - Kousa, A.I.*
AU  - Jahn, L.*
AU  - Zhao, K.*
AU  - Flores, A.E.*
AU  - Acenas, D.*
AU  - Lederer, E.*
AU  - Argyropoulos, K.V.*
AU  - Lemarquis, A.L.*
AU  - Granadier, D.*
AU  - Cooper, K.*
AU  - D'Andrea, M.*
AU  - Sheridan, J.M.*
AU  - Tsai, J.*
AU  - Sikkema, L.
AU  - Lazrak, A.*
AU  - Nichols, K.*
AU  - Lee, N.*
AU  - Ghale, R.*
AU  - Malard, F.*
AU  - Andrlova, H.*
AU  - Velardi, E.*
AU  - Youssef, S.A.*
AU  - Burgos da Silva, M.*
AU  - Docampo, M.*
AU  - Sharma, R.*
AU  - Mazutis, L.*
AU  - Wimmer, V.C.*
AU  - Rogers, K.L.*
AU  - DeWolf, S.*
AU  - Gipson, B.*
AU  - Gomes, A.L.C.*
AU  - Setty, M.*
AU  - Pe'er, D.*
AU  - Hale, L.*
AU  - Manley, N.R.*
AU  - Gray, D.H.D.*
AU  - van den Brink, M.R.M.*
AU  - Dudakov, J.A.*
C1  - 71439
C2  - 56174
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1593-1606
TI  - Age-related epithelial defects limit thymic function and regeneration.
JO  - Nat. Immunol.
VL  - 25
IS  - 9
PB  - Nature Portfolio
PY  - 2024
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
AU  - Soll, D.*
AU  - Chu, C.F.*
AU  - Sun, S.*
AU  - Lutz, V.*
AU  - Arunkumar, M.*
AU  - Gachechiladze, M.*
AU  - Schäuble, S.*
AU  - Alissa-Alkhalaf, M.*
AU  - Nguyen, T.*
AU  - Khalil, M.A.*
AU  - Garcia-Ribelles, I.*
AU  - Mueller, M.*
AU  - Buder, K.*
AU  - Michalke, B.
AU  - Panagiotou, G.*
AU  - Ziegler-Martin, K.*
AU  - Benz, P.*
AU  - Schatzlmaier, P.*
AU  - Hiller, K.*
AU  - Stockinger, H.*
AU  - Luu, M.*
AU  - Schober, K.*
AU  - Moosmann, C.*
AU  - Schamel, W.W.*
AU  - Huber, M.*
AU  - Zielinski, C.E.*
C1  - 71566
C2  - 56116
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
JO  - Nat. Immunol.
PB  - Nature Portfolio
PY  - 2024
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.
AU  - Chao, Y.Y.*
AU  - Puhach, A.*
AU  - Frieser, D.*
AU  - Arunkumar, M.*
AU  - Lehner, L.*
AU  - Seeholzer, T.
AU  - Garcia-Lopez, A.*
AU  - van der Wal, M.*
AU  - Fibi-Smetana, S.*
AU  - Dietschmann, A.*
AU  - Sommermann, T.*
AU  - Cikovic, T.*
AU  - Taher, L.*
AU  - Gresnigt, M.S.*
AU  - Vastert, S.J.*
AU  - van Wijk, F.*
AU  - Panagiotou, G.*
AU  - Krappmann, D.
AU  - Groß, O.*
AU  - Zielinski, C.E.*
C1  - 67184
C2  - 54234
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation.
JO  - Nat. Immunol.
VL  - 24
IS  - 2
PB  - Nature Portfolio
PY  - 2023
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Obesity-related metabolic organ inflammation contributes to cardiometabolic disorders. In obese individuals, changes in lipid fluxes and storage elicit immune responses in the adipose tissue (AT), including expansion of immune cell populations and qualitative changes in the function of these cells. Although traditional models of metabolic inflammation posit that these immune responses disturb metabolic organ function, studies now suggest that immune cells, especially AT macrophages (ATMs), also have important adaptive functions in lipid homeostasis in states in which the metabolic function of adipocytes is taxed. Adverse consequences of AT metabolic inflammation might result from failure to maintain local lipid homeostasis and long-term effects on immune cells beyond the AT. Here we review the complex function of ATMs in AT homeostasis and metabolic inflammation. Additionally, we hypothesize that trained immunity, which involves long-term functional adaptations of myeloid cells and their bone marrow progenitors, can provide a model by which metabolic perturbations trigger chronic systemic inflammation.
AU  - Chavakis, T.
AU  - Alexaki, V.I.*
AU  - Ferrante, A.W.*
C1  - 67631
C2  - 53938
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 757-766
TI  - Macrophage function in adipose tissue homeostasis and metabolic inflammation.
JO  - Nat. Immunol.
VL  - 24
IS  - 5
PB  - Nature Portfolio
PY  - 2023
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - In the version of the article initially published, there was an error in the project name listed in the Acknowledgements section. It has now been corrected to read “Our research is supported by the European Research Council (DEMETINL to T.C.) …” in the HTML and PDF versions of the article.
AU  - Chavakis, T.
AU  - Alexaki, V.I.*
AU  - Ferrante, A.W.*
C1  - 68953
C2  - 53893
TI  - Author Correction: Macrophage function in adipose tissue homeostasis and metabolic inflammation (Nature Immunology, (2023), 24, 5, (757-766), 10.1038/s41590-023-01479-0).
JO  - Nat. Immunol.
PY  - 2023
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
AU  - Zhao, J.H.*
AU  - Stacey, D.*
AU  - Eriksson, N.*
AU  - Macdonald-Dunlop, E.*
AU  - Hedman, *
AU  - Kalnapenkis, A.*
AU  - Enroth, S.*
AU  - Cozzetto, D.*
AU  - Digby-Bell, J.*
AU  - Marten, J.*
AU  - Folkersen, L.*
AU  - Herder, C.*
AU  - Jonsson, L.*
AU  - Bergen, S.E.*
AU  - Gieger, C.
AU  - Needham, E.J.*
AU  - Surendran, P.*
AU  - Paul, D.S.*
AU  - Polasek, O.*
AU  - Thorand, B.
AU  - Grallert, H.
AU  - Roden, M.*
AU  - Võsa, U.*
AU  - Esko, T.*
AU  - Hayward, C.*
AU  - Johansson, *
AU  - Gyllensten, U.*
AU  - Powell, N.*
AU  - Hansson, O.*
AU  - Mattsson-Carlgren, N.*
AU  - Joshi, P.K.*
AU  - Danesh, J.*
AU  - Padyukov, L.*
AU  - Klareskog, L.*
AU  - Landen, M.*
AU  - Wilson, J.F.*
AU  - Siegbahn, A.*
AU  - Wallentin, L.*
AU  - Mälarstig, A.*
AU  - Butterworth, A.S.*
AU  - Peters, J.E.*
C1  - 68008
C2  - 54486
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1540-1551
TI  - Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.
JO  - Nat. Immunol.
VL  - 24
IS  - 9
PB  - Nature Portfolio
PY  - 2023
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Correction to: Nature Immunology, published online 10 August 2023. In the version of the article originally published, the middle panel in Fig. 3b was mistakenly a duplicate of the upper panel. The figure has now been corrected in the HTML and PDF versions of the article.
AU  - Zhao, J.H.*
AU  - Stacey, D.*
AU  - Eriksson, N.*
AU  - Macdonald-Dunlop, E.*
AU  - Hedman, A.K.*
AU  - Kalnapenkis, A.*
AU  - Enroth, S.*
AU  - Cozzetto, D.*
AU  - Digby-Bell, J.*
AU  - Marten, J.*
AU  - Folkersen, L.*
AU  - Herder, C.*
AU  - Jonsson, L.*
AU  - Bergen, S.E.*
AU  - Gieger, C.
AU  - Needham, E.J.*
AU  - Surendran, P.*
AU  - Metspalu, A.*
AU  - Milani, L.*
AU  - Mägi, R.*
AU  - Nelis, M.*
AU  - Hudjašov, G.*
AU  - Paul, D.S.*
AU  - Polasek, O.*
AU  - Thorand, B.
AU  - Grallert, H.
AU  - Roden, M.*
AU  - Võsa, U.*
AU  - Esko, T.*
AU  - Hayward, C.*
AU  - Johansson, A.*
AU  - Gyllensten, U.*
AU  - Powell, N.*
AU  - Hansson, O.*
AU  - Mattsson-Carlgren, N.*
AU  - Joshi, P.K.*
AU  - Danesh, J.*
AU  - Padyukov, L.*
AU  - Klareskog, L.*
AU  - Landen, M.*
AU  - Wilson, J.F.*
AU  - Siegbahn, A.*
AU  - Wallentin, L.*
AU  - Mälarstig, A.*
AU  - Butterworth, A.S.*
AU  - Peters, J.E.*
C1  - 68301
C2  - 54726
TI  - Author Correction: Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets (Nature Immunology, (2023), 24, 9, (1540-1551), 10.1038/s41590-023-01588-w).
JO  - Nat. Immunol.
VL  - 24
IS  - 11
PY  - 2023
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Internal organs heal injuries with new connective tissue, but the cellular and molecular events of this process remain obscure. By tagging extracellular matrix around the mesothelium lining in mouse peritoneum, liver and cecum, here we show that preexisting matrix was transferred across organs into wounds in various injury models. Using proteomics, genetic lineage-tracing and selective injury in juxtaposed organs, we found that the tissue of origin for the transferred matrix likely dictated the scarring or regeneration of the healing tissue. Single-cell RNA sequencing and genetic and chemical screens indicated that the preexisting matrix was transferred by neutrophils dependent on the HSF-integrin AM/B2-kindlin3 cascade. Pharmacologic inhibition of this axis prevented matrix transfer and the formation of peritoneal adhesions. Matrix transfer was thus an early event of wound repair and provides a therapeutic window to dampen scaring across a range of conditions.
AU  - Fischer, A.
AU  - Wannemacher, J.
AU  - Christ, S.
AU  - Koopmans, T.*
AU  - Kadri, S.
AU  - Zhao, J.
AU  - Gouda, M.
AU  - Ye, H.
AU  - Mück-Häusl, M.
AU  - Krenn, P.W.*
AU  - Machens, H.*
AU  - Faessler, R.*
AU  - Neumann, P.*
AU  - Hauck, S.M.
AU  - Rinkevich, Y.
C1  - 64760
C2  - 51926
SP  - 518-531
TI  - Neutrophils direct preexisting matrix to initiate repair in damaged tissues.
JO  - Nat. Immunol.
VL  - 23
IS  - 4
PY  - 2022
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - T cell antigen-receptor (TCR) signaling controls the development, activation and survival of T cells by involving several layers and numerous mechanisms of gene regulation. N6-methyladenosine (m6A) is the most prevalent messenger RNA modification affecting splicing, translation and stability of transcripts. In the present study, we describe the Wtap protein as essential for m6A methyltransferase complex function and reveal its crucial role in TCR signaling in mouse T cells. Wtap and m6A methyltransferase functions were required for the differentiation of thymocytes, control of activation-induced death of peripheral T cells and prevention of colitis by enabling gut RORγt+ regulatory T cell function. Transcriptome and epitranscriptomic analyses reveal that m6A modification destabilizes Orai1 and Ripk1 mRNAs. Lack of post-transcriptional repression of the encoded proteins correlated with increased store-operated calcium entry activity and diminished survival of T cells with conditional genetic inactivation of Wtap. These findings uncover how m6A modification impacts on TCR signal transduction and determines activation and survival of T cells.
AU  - Ito-Kureha, T.*
AU  - Leoni, C.*
AU  - Borland, K.*
AU  - Cantini, G.
AU  - Bataclan, M.*
AU  - Metzger, R.N.*
AU  - Ammann, G.*
AU  - Krug, A.B.*
AU  - Marsico, A.
AU  - Kaiser, S.*
AU  - Canzar, S.*
AU  - Feske, S.*
AU  - Monticelli, S.*
AU  - König, J.*
AU  - Heissmeyer, V.
C1  - 65747
C2  - 52820
SP  - 1208-1221
TI  - The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells.
JO  - Nat. Immunol.
VL  - 23
IS  - 8
PY  - 2022
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The increasing implication of lymphocytes in general physiology and immune surveillance outside of infection poses the question of how their antigen receptors might be involved. Here, we show that macromolecular aggregates of intraepidermal γδ T cell antigen receptors (TCRs) in the mouse skin aligned with and depended on Skint1, a butyrophilin-like (BTNL) protein expressed by differentiated keratinocytes (KCs) at steady state. Interruption of TCR-mediated 'normality sensing' had no impact on γδ T cell numbers but altered their signature phenotype, while the epidermal barrier function was compromised. In addition to the regulation of steady-state physiology, normality sensing licensed intraepidermal T cells to respond rapidly to subsequent tissue perturbation by using innate tumor necrosis factor (TNF) superfamily receptors. Thus, interfering with Skint1-dependent interactions between local γδ T cells and KCs at steady state increased the susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation, two cancer-disposing factors.
AU  - McKenzie, D.R.*
AU  - Hart, R.*
AU  - Bah, N.*
AU  - Ushakov, D.S.*
AU  - Muñoz-Ruiz, M.*
AU  - Feederle, R.
AU  - Hayday, A.C.*
C1  - 64369
C2  - 51914
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 411–422
TI  - Normality sensing licenses local T cells for innate-like tissue surveillance.
JO  - Nat. Immunol.
VL  - 23
PB  - Nature Portfolio
PY  - 2022
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.
AU  - Behrens, G.*
AU  - Edelmann, S.L.
AU  - Raj, T.*
AU  - Kronbeck, N.*
AU  - Monecke, T.*
AU  - Davydova, E.-O.
AU  - Wong, E.H.*
AU  - Kifinger, L.
AU  - Giesert, F.
AU  - Kirmaier, M.E.*
AU  - Hohn, C.*
AU  - de Jonge, L.S.
AU  - Pisfil, M.G.*
AU  - Fu, M.*
AU  - Theurich, S.*
AU  - Feske, S.*
AU  - Kawakami, N.*
AU  - Wurst, W.
AU  - Niessing, D.
AU  - Heissmeyer, V.
C1  - 63617
C2  - 51605
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1563-1576
TI  - Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.
JO  - Nat. Immunol.
VL  - 22
IS  - 12
PB  - Nature Portfolio
PY  - 2021
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
AU  - Peng, Y.*
AU  - Felce, S.L.*
AU  - Dong, D.*
AU  - Penkava, F.*
AU  - Mentzer, A.J.*
AU  - Yao, X.*
AU  - Liu, G.*
AU  - Yin, Z.*
AU  - Chen, J.L.*
AU  - Lu, Y.*
AU  - Wellington, D.*
AU  - Wing, P.A.C.*
AU  - Dominey-Foy, D.C.C.*
AU  - Jin, C.*
AU  - Wang, W.*
AU  - Hamid, M.A.*
AU  - Fernandes, R.A.*
AU  - Wang, B.*
AU  - Fries, A.*
AU  - Zhuang, X.*
AU  - Ashley, N.*
AU  - Rostron, T.*
AU  - Waugh, C.*
AU  - Sopp, P.*
AU  - Hublitz, P.*
AU  - Beveridge, R.*
AU  - Tan, T.K.*
AU  - Dold, C.*
AU  - Kwok, A.J.*
AU  - Rich-Griffin, C.*
AU  - Dejnirattisa, W.*
AU  - Liu, C.*
AU  - Kurupati, P.*
AU  - Nassiri, I.*
AU  - Watson, R.A.*
AU  - Tong, O.*
AU  - Taylor, C.A.*
AU  - Kumar Sharma, P.*
AU  - Sun, B.*
AU  - Curion, F.
AU  - Revale, S.*
AU  - Garner, L.C.*
AU  - Jansen, K.*
AU  - Ferreira, R.C.*
AU  - Attar, M.*
AU  - Fry, J.W.*
AU  - Russell, R.A.*
AU  - COMBAT Consortium*
AU  - Stauss, H.J.*
AU  - James, W.*
AU  - Townsend, A.J.*
AU  - Ho, J.-P.*
AU  - Klenerman, P.*
AU  - Mongkolsapaya, J.*
AU  - Screaton, G.R.*
AU  - Dendrou, C.*
AU  - Sansom, S.N.*
AU  - Bashford-Rogers, R.*
AU  - Chain, B.*
AU  - Smith, G.L.*
AU  - McKeating, J.A.*
AU  - Fairfax, B.P.*
AU  - Bowness, P.*
AU  - McMichael, A.J.*
AU  - Ogg, G.*
AU  - Knight, J.C.*
AU  - Dong, T.*
C1  - 63731
C2  - 51498
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.
JO  - Nat. Immunol.
PB  - Nature Portfolio
PY  - 2021
SN  - 1529-2908
ER  - 

TY  - JOUR
AU  - Schiller, H. B.
AU  - van Breugel, M.*
AU  - Nawijn, M.C.*
C1  - 62313
C2  - 50713
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 806-808
TI  - SARS-CoV-2-specific hotspots in virus-host interaction networks.
JO  - Nat. Immunol.
VL  - 22
IS  - 7
PB  - Nature Research
PY  - 2021
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8(+) T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8(+) T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.Myeloid-derived suppressor cells (MDSCs) residing within tumors can impede immune responses. Knolle and colleagues show that MDSCs poison immune cells by producing methylglyoxal, which functionally alters their cellular metabolism and hence their effector responses.
AU  - Baumann, T.*
AU  - Dunkel, A.*
AU  - Schmid, C.*
AU  - Schmitt, S.*
AU  - Hiltensperger, M.*
AU  - Lohr, K.*
AU  - Laketa, V.*
AU  - Donakonda, S.*
AU  - Ahting, U.*
AU  - Lorenz-Depiereux, B.
AU  - Heil, J.E.*
AU  - Schredelseker, J.*
AU  - Simeoni, L.*
AU  - Fecher, C.*
AU  - Körber, N.
AU  - Bauer, T.
AU  - Hüser, N.*
AU  - Hartmann, D.*
AU  - Laschinger, M.*
AU  - Eyerich, K.*
AU  - Eyerich, S.
AU  - Anton, M.*
AU  - Streeter, M.*
AU  - Wang, T.*
AU  - Schraven, B.*
AU  - Spiegel, D.*
AU  - Assaad, F.*
AU  - Misgeld, T.*
AU  - Zischka, H.
AU  - Murray, P.J.*
AU  - Heine, A.*
AU  - Heikenwälder, M.*
AU  - Korn, T.*
AU  - Dawid, C.*
AU  - Hofmann, T.*
AU  - Knolle, P.A.*
AU  - Höchst, B.*
C1  - 58938
C2  - 48566
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 555-566
TI  - Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.
JO  - Nat. Immunol.
VL  - 21
IS  - 5
PB  - Nature Publishing Group
PY  - 2020
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - An amendment to this paper has been published and can be accessed via a link at the top of the paper.
AU  - Beyer, M.*
AU  - Abdullah, Z.*
AU  - Chemnitz, J.M.*
AU  - Maisel, D.*
AU  - Sander, J.*
AU  - Lehmann, C.*
AU  - Thabet, Y.*
AU  - Shinde, P.V.*
AU  - Schmidleithner, L.*
AU  - Köhne, M.*
AU  - Trebicka, J.*
AU  - Schierwagen, R.*
AU  - Hofmann, A.*
AU  - Popov, A.*
AU  - Lang, K.S.*
AU  - Oxenius, A.*
AU  - Buch, T.*
AU  - Kurts, C.*
AU  - Heikenwälder, M.
AU  - Fätkenheuer, G.*
AU  - Lang, P.A.*
AU  - Hartmann, P.*
AU  - Knolle, P.A.*
AU  - Schultze, J.L.*
C1  - 59604
C2  - 48870
TI  - Publisher Correction: Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection (Nature Immunology, (2016), 17, 5, (593-603), 10.1038/ni.3399).
JO  - Nat. Immunol.
PY  - 2020
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystalinduced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a proresolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.
AU  - Kourtzelis, I.*
AU  - Li, X.*
AU  - Mitroulis, I.*
AU  - Grosser, D.
AU  - Kajikawa, T.*
AU  - Wang, B.*
AU  - Grzybek, M.
AU  - von Renesse, J.*
AU  - Czogalla, A.*
AU  - Troullinaki, M.*
AU  - Ferreira, A.*
AU  - Doreth, C.*
AU  - Ruppova, K.*
AU  - Chen, L.S.*
AU  - Hosur, K.*
AU  - Lim, J.H.*
AU  - Chung, K.-J.
AU  - Grossklaus, S.*
AU  - Tausche, A.K.*
AU  - Joosten, L.A.B.*
AU  - Moutsopoulos, N.M.*
AU  - Wielockx, B.*
AU  - Castrillo, A.*
AU  - Korostoff, J.M.*
AU  - Coskun, Ü.
AU  - Hajishengallis, G.*
AU  - Chavakis, T.*
C1  - 54796
C2  - 45838
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 40-49
TI  - DEL-1 promotes macrophage efferocytosis and clearance of inflammation.
JO  - Nat. Immunol.
VL  - 20
IS  - 1
PB  - Nature Publishing Group
PY  - 2019
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Antibody affinity maturation occurs in germinal centers (GCs), where B cells cycle between the light zone (LZ) and the dark zone. In the LZ, GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from helper T cells, which promotes their rapid proliferation. Here we found that the RNA-binding protein PTBP1 was needed for the progression of GC B cells through late S phase of the cell cycle and for affinity maturation. PTBP1 was required for proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulated the alternative splicing and abundance of transcripts that are increased during positive selection to promote proliferation.
AU  - Monzón-Casanova, E.*
AU  - Screen, M.*
AU  - Díaz-Muñoz, M.D.*
AU  - Coulson, R.M.R.*
AU  - Bell, S.E.*
AU  - Lamers, G.*
AU  - Solimena, M.
AU  - Smith, C.W.J.*
AU  - Turner, M.*
C1  - 53087
C2  - 44328
CY  - New York
SP  - 267–278
TI  - The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers.
JO  - Nat. Immunol.
VL  - 19
IS  - 3
PB  - Nature Publishing Group
PY  - 2018
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - In contrast to most other malignancies, hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancers, arises almost exclusively in the setting of chronic inflammation. Irrespective of etiology, a typical sequence of chronic necroinflammation, compensatory liver regeneration, induction of liver fibrosis and subsequent cirrhosis often precedes hepatocarcinogenesis. The liver is a central immunomodulator that ensures organ and systemic protection while maintaining immunotolerance. Deregulation of this tightly controlled liver immunological network is a hallmark of chronic liver disease and HCC. Notably, immunotherapies have raised hope for the successful treatment of advanced HCC. Here we summarize the roles of specific immune cell subsets in chronic liver disease, with a focus on non-alcoholic steatohepatitis and HCC. We review new advances in immunotherapeutic approaches for the treatment of HCC and discuss the challenges posed by the immunotolerant hepatic environment and the dual roles of adaptive and innate immune cells in HCC.
AU  - Ringelhan, M.
AU  - Pfister, D.*
AU  - O'Connor, T.
AU  - Pikarsky, E.*
AU  - Heikenwalder, M.*
C1  - 52871
C2  - 44605
CY  - New York
SP  - 222-232
TI  - The immunology of hepatocellular carcinoma.
JO  - Nat. Immunol.
VL  - 19
IS  - 3
PB  - Nature Publishing Group
PY  - 2018
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis–associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1−/− mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.
AU  - Abdul-Sater, A.A.*
AU  - Edilova, M.I.*
AU  - Clouthier, D.L.*
AU  - Mbanwi, A.*
AU  - Kremmer, E.
AU  - Watts, T.H.*
C1  - 50266
C2  - 42069
SP  - 26-35
TI  - The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease.
JO  - Nat. Immunol.
VL  - 18
PY  - 2017
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin alpha(4) and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin alpha(4) in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.
AU  - Chung, K.-J.
AU  - Chatzigeorgiou, A.*
AU  - Economopoulou, M.*
AU  - Garcia-Martin, R.*
AU  - Alexaki, V.I.*
AU  - Mitroulis, I.*
AU  - Nati, M.*
AU  - Gebler, J.*
AU  - Ziemssen, T.*
AU  - Goelz, S.E.*
AU  - Phieler, J.*
AU  - Lim, J.H.*
AU  - Karalis, K.P.*
AU  - Papayannopoulou, T.*
AU  - Blueher, M.*
AU  - Hajishengallis, G.*
AU  - Chavakis, T.
C1  - 51265
C2  - 42950
CY  - New York
SP  - 654-664
TI  - A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.
JO  - Nat. Immunol.
VL  - 18
IS  - 6
PB  - Nature Publishing Group
PY  - 2017
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5(-/-) mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5(-/-) mice. This pathway, which we have called 'oxeiptosis', was a ROS-sensitive, caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens.
AU  - Holze, C.*
AU  - Michaudel, C.*
AU  - Mackowiak, C.*
AU  - Haas, D.A.*
AU  - Benda, C.*
AU  - Hubel, P.*
AU  - Pennemann, F.L.*
AU  - Schnepf, D.*
AU  - Wettmarshausen, J.
AU  - Braun, M.*
AU  - Leung, D.W.*
AU  - Amarasinghe, G.K.*
AU  - Perocchi, F.
AU  - Staeheli, P.*
AU  - Ryffel, B.*
AU  - Pichlmair, A.*
C1  - 52597
C2  - 44094
CY  - New York
SP  - 130–140
TI  - Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway.
JO  - Nat. Immunol.
VL  - 19
IS  - 2
PB  - Nature Publishing Group
PY  - 2017
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity-infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)-we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.
AU  - Beyer, M.*
AU  - Abdullah, Z.*
AU  - Chemnitz, J.M.*
AU  - Maisel, D.*
AU  - Sander, J.*
AU  - Lehmann, C.*
AU  - Thabet, Y.*
AU  - Shinde, P.V.*
AU  - Schmidleithner, L.*
AU  - Köhne, M.*
AU  - Trebicka, J.*
AU  - Schierwagen, R.*
AU  - Hofmann, A.*
AU  - Popov, A.*
AU  - Lang, K.S.*
AU  - Oxenius, A.*
AU  - Buch, T.*
AU  - Kurts, C.*
AU  - Heikenwälder, M.
AU  - Fätkenheuer, G.*
AU  - Lang, P.A.*
AU  - Hartmann, P.*
AU  - Knolle, P.A.*
AU  - Schultze, J.L.*
C1  - 48056
C2  - 39881
CY  - New York
SP  - 593-603
TI  - Tumor-necrosis factor impairs CD4+ T cell-mediated immunological control in chronic viral infection.
JO  - Nat. Immunol.
VL  - 17
IS  - 5
PB  - Nature Publishing Group
PY  - 2016
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.
AU  - Finkin, S.*
AU  - Yuan, D.T.
AU  - Stein, I.*
AU  - Taniguchi, K.*
AU  - Weber, A.*
AU  - Unger, K.
AU  - Browning, J.L.*
AU  - Goossens, N.*
AU  - Nakagawa, S.*
AU  - Gunasekaran, G.*
AU  - Schwartz, M.E.*
AU  - Kobayashi, M.*
AU  - Kumada, H.*
AU  - Berger, M.*
AU  - Pappo, O.*
AU  - Rajewsky, K.*
AU  - Hoshida, Y.*
AU  - Karin, M.*
AU  - Heikenwälder, M.
AU  - Ben-Neriah, Y.*
AU  - Pikarsky, E.*
C1  - 47235
C2  - 39241
SP  - 1235-1244
TI  - Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.
JO  - Nat. Immunol.
VL  - 16
IS  - 12
PY  - 2015
SN  - 1529-2908
ER  - 

TY  - JOUR
AU  - Flossdorf, M.*
AU  - Rössler, J.*
AU  - Buchholz, V.R.*
AU  - Busch, D.H.
AU  - Höfer, T.*
C1  - 46605
C2  - 37664
SP  - 891-893
TI  - CD8+ T cell diversification by asymmetric cell division.
JO  - Nat. Immunol.
VL  - 16
IS  - 9
PY  - 2015
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (TFH cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the TH17 subset of helper T cells in the lungs. Roquin inhibited TH17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the TH17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance TH17 differentiation.
AU  - Jeltsch, K.
AU  - Hu, D.
AU  - Brenner, S.
AU  - Zöller, J.
AU  - Heinz, G.A.
AU  - Nagel, D.
AU  - Vogel, K.U.
AU  - Rehage, N.
AU  - Warth, S.C.
AU  - Edelmann, S.L.
AU  - Gloury, R.*
AU  - Martin, N.
AU  - Lohs, C.
AU  - Lech, M.*
AU  - Stehklein, J.E.
AU  - Geerlof, A.
AU  - Kremmer, E.
AU  - Weber, A.*
AU  - Anders, H.J.*
AU  - Schmitz, I.*
AU  - Schmidt-Supprian, M.*
AU  - Fu, M.*
AU  - Holtmann, H.*
AU  - Krappmann, D.
AU  - Ruland, J.*
AU  - Kallies, A.*
AU  - Heikenwälder, M.
AU  - Heissmeyer, V.
C1  - 32469
C2  - 35065
CY  - New York
SP  - 1079-1089
TI  - Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation.
JO  - Nat. Immunol.
VL  - 15
IS  - 11
PB  - Nature Publishing Group
PY  - 2014
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1β (IL-1β) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. Transfection of dendritic cells with dsDNA or infection of dendritic cells with a DNA virus induced the formation of dsDNA-Rad50-CARD9 signaling complexes for activation of the transcription factor NF-κB and the generation of pro-IL-1β. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1β, and Card9(-/-) mice had impaired inflammatory responses after infection with a DNA virus in vivo. Our results define a cytosolic DNA-recognition pathway for inflammation and a physical and functional connection between a conserved DNA-damage sensor and the innate immune response to pathogens.
AU  - Roth, S.*
AU  - Rottach, A.*
AU  - Lotz-Havla, A.S.*
AU  - Laux, V.*
AU  - Muschaweckh, A.
AU  - Gersting, S.W.*
AU  - Muntau, A.C.*
AU  - Hopfner, K.P.*
AU  - Jin, L.*
AU  - Vanness, K.*
AU  - Petrini, J.H.*
AU  - Drexler, I.
AU  - Leonhardt, H.*
AU  - Ruland, J.*
C1  - 31172
C2  - 34219
CY  - New York
SP  - 538-545
TI  - Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production.
JO  - Nat. Immunol.
VL  - 15
IS  - 6
PB  - Nature Publishing Group
PY  - 2014
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8+ T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b+ cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.
AU  - Huang, L.R.*
AU  - Wohlleber, D.*
AU  - Reisinger, F.
AU  - Jenne, C.N.*
AU  - Cheng, R.L.*
AU  - Abdullah, Z.*
AU  - Schildberg, F.A.*
AU  - Odenthal, M.*
AU  - Dienes, H.P.*
AU  - van Rooijen, N.*
AU  - Schmitt, E.*
AU  - Garbi, N.*
AU  - Croft, M.*
AU  - Kurts, C.*
AU  - Kubes, P.*
AU  - Protzer, U.
AU  - Heikenwälder, M.
AU  - Knolle, P.A.*
C1  - 24024
C2  - 31309
SP  - 574-583
TI  - Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection.
JO  - Nat. Immunol.
VL  - 14
IS  - 6
PB  - Nature Publishing
PY  - 2013
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Activation of NF-κB transcription factors by receptors of the innate or adaptive immune system is essential for host defense. However, after danger is eliminated, NF-κB signaling needs to be tightly downregulated for the maintenance of tissue homeostasis. This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-κB-activating proteins to attenuate the NF-κB response. These mechanisms are needed to prevent inflammation, autoimmune disease and oncogenesis.
AU  - Ruland, J.
C1  - 6352
C2  - 29049
CY  - New York, NY, USA
SP  - 709-714
TI  - Return to homeostasis: Downregulation of NF-κB responses.
JO  - Nat. Immunol.
VL  - 12
IS  - 8
PB  - Nature America Inc.
PY  - 2011
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8(+) T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α(+) DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α(+) DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other Gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.
AU  - Verschoor, A.
AU  - Neuenhahn, M.
AU  - Navarini, A.A.*
AU  - Graef, P.*
AU  - Plaumann, A.*
AU  - Seidlmeier, A.*
AU  - Nieswandt, B.*
AU  - Massberg, S.*
AU  - Zinkernagel, R.M.*
AU  - Hengartner, H.*
AU  - Busch, D.H.
C1  - 6815
C2  - 29310
SP  - 1194-1201
TI  - A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3.
JO  - Nat. Immunol.
VL  - 12
IS  - 12
PB  - Nature Publishing Group
PY  - 2011
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The molecular mechanism by which roquin controls the expression of inducible costimulator (ICOS) to prevent autoimmunity remains unsolved. Here we show that in helper T cells, roquin localized to processing (P) bodies and downregulated ICOS expression. The repression was dependent on the RNA helicase Rck, and roquin interacted with Rck and the enhancer of decapping Edc4, which act together in mRNA decapping. Sequences in roquin that confer P-body localization were essential for roquin-mediated ICOS repression. However, this process did not require microRNAs or the RNA-induced silencing complex (RISC). Instead, roquin bound ICOS mRNA directly, showing an intrinsic preference for a previously unrecognized sequence in the 3' untranslated region (3' UTR). Our results support a model in which roquin controls ICOS expression through binding to the 3' UTR of ICOS mRNA and by interacting with proteins that confer post-transcriptional repression.
AU  - Glasmacher, E.
AU  - Höfig, K.P.
AU  - Vogel, K.U.
AU  - Rath, N.
AU  - Du, L.
AU  - Wolf, C.
AU  - Kremmer, E.
AU  - Wang, X.*
AU  - Heissmeyer, V.
C1  - 122
C2  - 27340
SP  - 725-733
TI  - Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression.
JO  - Nat. Immunol.
VL  - 11
IS  - 8
PB  - Nature Publ. Group
PY  - 2010
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.
AU  - Poeck, H.*
AU  - Bscheider, M.*
AU  - Gross, O.*
AU  - Finger, K.*
AU  - Roth, S.
AU  - Rebsamen, M.*
AU  - Hannesschläger, N.*
AU  - Schlee, M.*
AU  - Rothenfusser, S.*
AU  - Barchet, W.*
AU  - Kato, H.*
AU  - Akira, S.*
AU  - Inoue, S.*
AU  - Endres, S.*
AU  - Peschel, C.*
AU  - Hartmann, G.*
AU  - Hornung, V.*
AU  - Ruland, J.
C1  - 5578
C2  - 27788
SP  - 63-69
TI  - Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production.
JO  - Nat. Immunol.
VL  - 11
IS  - 1
PB  - Nature America Inc.
PY  - 2010
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - The recirculation of leukocytes is essential for proper immune responses. However, the molecular mechanisms that regulate the entry of leukocytes into the lymphatics remain unclear. Here we show that plexin-A1, a principal receptor component for class III and class VI semaphorins, was crucially involved in the entry of dendritic cells (DCs) into the lymphatics. Additionally, we show that the semaphorin Sema3A, but not Sema6C or Sema6D, was required for DC transmigration and that Sema3A produced by the lymphatics promoted actomyosin contraction at the trailing edge of migrating DCs. Our findings not only demonstrate that semaphorin signals are involved in DC trafficking but also identify a previously unknown mechanism that induces actomyosin contraction as these cells pass through narrow gaps.
AU  - Takamatsu, H.*
AU  - Takegahara, N.*
AU  - Nakagawa, Y.*
AU  - Tomura, M.*
AU  - Taniguchi, M.*
AU  - Friedel, R.H.
AU  - Rayburn, H.*
AU  - Tessier-Lavigne, M.*
AU  - Yoshida, Y.*
AU  - Okuno, T.*
AU  - Mizui, M.*
AU  - Kang, S.*
AU  - Nojima, S.*
AU  - Tsujimura, T.*
AU  - Nakatsuji, Y.*
AU  - Katayama, I.*
AU  - Toyofuku, T.*
AU  - Kikutani, H.*
AU  - Kumanogoh, A.*
C1  - 1014
C2  - 27371
SP  - 594-560
TI  - Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II.
JO  - Nat. Immunol.
VL  - 11
IS  - 7
PB  - Nature Publ. Group
PY  - 2010
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - Both activation and termination of transcription factor NF-kB signaling require ubiquitin modification of pathway components. The E3 ligase Itch teams up with the NF-kB inhibitor A20 to edit the composition of ubiquitin chains on the signaling adaptor RIP, thereby limiting inflammatory responses.
AU  - Heissmeyer, V.
AU  - Rao, A.
C1  - 3385
C2  - 25133
SP  - 227-229
TI  - Itching to end NF-kB.
JO  - Nat. Immunol.
VL  - 9
IS  - 3
PB  - Nature Publ. Group
PY  - 2008
SN  - 1529-2908
ER  - 

TY  - JOUR
AB  - NF-kappaB (Rel) transcription factors control physiological and pathological immune cell function. The scaffold proteins Bcl-10 and MALT1 couple antigen-receptor signals to the canonical NF-kappaB pathway and are pivotal in lymphomagenesis. Here we found that Bcl-10 and MALT1 differentially regulated B cell receptor–induced activation of RelA and c-Rel. Bcl-10 was essential for recruitment of the kinase IKK into lipid rafts for the activation of RelA and c-Rel, for blocking apoptosis and for inducing division after B cell receptor ligation. In contrast, MALT1 participated in survival signaling but was not involved in IKK recruitment or activation and was dispensable for RelA induction and proliferation. MALT1 selectively activated c-Rel to control a distinct subprogram. Our results provide mechanistic insights into B cell receptor–induced survival and proliferation signals and demonstrate the selective control of c-Rel in the canonical NF-kappaB pathway.
AU  - Ferch, U.*
AU  - Meyer zum Büschenfelde, C.*
AU  - Gewies, A.*
AU  - Wegener, E.
AU  - Rauser, S.
AU  - Peschel, C.*
AU  - Krappmann, D.
AU  - Ruland, J.*
C1  - 2968
C2  - 24527
SP  - 984-991
TI  - MALT1 directs B cell receptor–induced canonical nuclear factor-kappaB signaling selectively to the c-Rel subunit.
JO  - Nat. Immunol.
VL  - 8
IS  - 9
PB  - Nature Publ. Group
PY  - 2007
SN  - 1529-2908
ER  -