TY  - JOUR
AB  - The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri (Hpb), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme's catalytic activity suppressed the synthesis of type 2-promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.
AU  - Bohnacker, S.
AU  - Henkel, F.
AU  - Hartung, F.
AU  - Geerlof, A.
AU  - Riemer, S.
AU  - Prodjinotho, U.F.*
AU  - Salah, E.B.*
AU  - Mourao, A.
AU  - Bohn, S.
AU  - Teder, T.*
AU  - Thomas, D.*
AU  - Gurke, R.*
AU  - Böckel, C.
AU  - Ud-Dean, M.
AU  - König, A.-C.
AU  - Quaranta, A.*
AU  - Alessandrini, F.
AU  - Lechner, A.
AU  - Spitzlberger, B.
AU  - Kabat, A.M.*
AU  - Pearce, E.J.*
AU  - Haeggström, J.Z.*
AU  - Hauck, S.M.
AU  - Wheelock, C.E.*
AU  - Jakobsson, P.J.*
AU  - Sattler, M.
AU  - Voehringer, D.*
AU  - Feige, M.J.*
AU  - da Costa, C.P.*
AU  - Esser-von Bieren, J.
C1  - 72671
C2  - 56706
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.
JO  - Sci. Immunol.
VL  - 9
IS  - 102
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - T follicular helper (TFH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse TFH cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor-β (TGF-β) induces robust expression of TFH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4+ T cells in vitro. TGF-β-induced mouse CXCR5+ TFH cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated TFH cells and provide critical help to B cells. The study further reveals that TGF-β-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-β-containing T helper 17 (TH17)-inducing conditions also yield separate CXCR5+ and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of TFH and TH17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced TFH cell program, that TFH and TH17 cells share a common developmental stage, and that c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-β-rich environments in vitro and in vivo.
AU  - Chang, Y.*
AU  - Bach, L.*
AU  - Hasiuk, M.*
AU  - Wen, L.*
AU  - Elmzzahi, T.*
AU  - Tsui, C.*
AU  - Gutiérrez-Melo, N.*
AU  - Steffen, T.*
AU  - Utzschneider, D.T.*
AU  - Raj, T.*
AU  - Jost, P.J.*
AU  - Heink, S.*
AU  - Cheng, J.*
AU  - Burton, O.T.*
AU  - Zeiträg, J.*
AU  - Alterauge, D.*
AU  - Dahlström, F.*
AU  - Becker, J.C.*
AU  - Kastl, M.*
AU  - Symeonidis, K.*
AU  - van Uelft, M.*
AU  - Becker, M.*
AU  - Reschke, S.*
AU  - Krebs, S.*
AU  - Blum, H.*
AU  - Abdullah, Z.*
AU  - Paeschke, K.*
AU  - Ohnmacht, C.
AU  - Neumann, C.*
AU  - Liston, A.*
AU  - Meissner, F.*
AU  - Korn, T.*
AU  - Hasenauer, J.
AU  - Heissmeyer, V.
AU  - Beyer, M.*
AU  - Kallies, A.*
AU  - Jeker, L.T.*
AU  - Baumjohann, D.*
C1  - 70092
C2  - 55416
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf.
JO  - Sci. Immunol.
VL  - 9
IS  - 93
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for host defense in a wide variety of tissues and barrier sites. Insights into the maintenance and regulatory checkpoints of human TRM cells remain scarce, especially due to the difficulties associated with tracking T cells through time and space in humans. We therefore sought to identify and characterize skin-resident T cells in humans defined by their long-term in situ lodgment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) preceded by myeloablative chemotherapy unmasked long-term sequestration of host T cell subsets in human skin despite complete donor T cell chimerism in the blood. Single-cell chimerism analysis paired with single-cell transcriptional profiling comprehensively characterized these bona fide long-term skin-resident T cells and revealed differential tissue maintenance for distinct T cell subsets, specific TRM cell markers such as galectin-3, but also tissue exit potential with retention of the transcriptomic TRM cell identity. Analysis of 26 allo-HSCT patients revealed profound interindividual variation in the tissue maintenance of host skin T cells. The long-term persistence of host skin T cells in a subset of these patients did not correlate with the development of chronic GvHD. Our data exemplify the power of exploiting a clinical situation as a proof of concept for the existence of bona fide human skin TRM cells and reveal long-term persistence of host T cells in a peripheral tissue but not in the circulation or bone marrow in a subset of allo-HSCT patients.
AU  - de Almeida, G.P.*
AU  - Lichtner, P.
AU  - Eckstein, G.N.
AU  - Brinkschmidt, T.*
AU  - Chu, C.F.*
AU  - Sun, S.*
AU  - Reinhard, J.*
AU  - Mädler, S.C.*
AU  - Kloeppel, M.*
AU  - Verbeek, M.*
AU  - Zielinski, C.E.*
C1  - 64215
C2  - 51805
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential.
JO  - Sci. Immunol.
VL  - 7
IS  - 67
PB  - Amer Assoc Advancement Science
PY  - 2022
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - New research shows that specialized epithelial cells (tuft cells) are 
      major producers of lipid mediators (leukotrienes) that drive allergic 
      inflammation and host defense against helminth parasites. (See the 
      related Research Article by Ualiyeva et al.)
AU  - Henkel, F.*
AU  - Esser-von Bieren, J.*
C1  - 64005
C2  - 51820
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Not just "leuko" after all: Epithelial leukotriene production in type 2 immunity.
JO  - Sci. Immunol.
VL  - 7
IS  - 67
PB  - Amer Assoc Advancement Science
PY  - 2022
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLRs), leading to induction of type I interferons (IFN-Is), proinflammatory cytokines, and apoptosis. Here, we elucidate signaling mechanisms that lead to cytokine secretion and cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA) in tumor cells. We show that both outcomes are mediated by dsRNA-receptor families with RLR being essential for cytokine production and IFN-I-mediated priming of effector pathways but not for apoptosis. Affinity purification followed by mass spectrometry and subsequent functional analysis revealed that 3p-RNA bound and activated oligoadenylate synthetase 1 and RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and up-regulation of NOXA was needed to deplete the antiapoptotic MCL-1 to cause intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of RIG-I-dependent priming and an RNase L-dependent effector phase.
AU  - Boehmer, D.F.R.*
AU  - Formisano, S.*
AU  - de Oliveira Mann, C.C.*
AU  - Mueller, S.A.*
AU  - Kluge, M.*
AU  - Metzger, P.*
AU  - Rohlfs, M.*
AU  - Hörth, C.*
AU  - Kocheise, L.*
AU  - Lichtenthaler, S.F.*
AU  - Hopfner, K.P.*
AU  - Endres, S.
AU  - Rothenfußer, S.
AU  - Friedel, C.C.*
AU  - Duewell, P.*
AU  - Schnurr, M.*
AU  - Koenig, L.M.*
C1  - 62563
C2  - 50945
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis.
JO  - Sci. Immunol.
VL  - 6
IS  - 61
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - Balanced control of T cell signaling is critical for adaptive immunity 
      and protection from autoimmunity. By combining genetically engineered 
      mouse models, biochemical analyses and pharmacological interventions, we
       describe an unexpected dual role of the tumor necrosis factor 
      receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and 
      negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) 
      paracaspase. Although MALT1-TRAF6 recruitment is indispensable for 
      nuclear factor κB signaling in activated T cells, TRAF6 counteracts 
      basal MALT1 protease activity in resting T cells. In mice, loss of 
      TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe
       autoimmune inflammation, which is completely reverted by genetic or 
      therapeutic inactivation of MALT1 protease function. Thus, TRAF6 
      functions as a molecular brake for MALT1 protease in resting T cells and
       a signaling accelerator for MALT1 scaffolding in activated T cells, 
      revealing that TRAF6 controls T cell activation in a switch-like manner.
       Our findings have important implications for development and treatment 
      of autoimmune diseases.
AU  - O'Neill, T.J.
AU  - Seeholzer, T.
AU  - Gewies, A.
AU  - Gehring, T.
AU  - Giesert, F.
AU  - Hamp, I.
AU  - Grass, C.
AU  - Schmidt, H.*
AU  - Kriegsmann, K.*
AU  - Tofaute, M.J.
AU  - Demski, K.
AU  - Poth, T.*
AU  - Rosenbaum, M.*
AU  - Schnalzger, T.*
AU  - Ruland, J.*
AU  - Göttlicher, M.
AU  - Kriegsmann, M.*
AU  - Naumann, R.*
AU  - Heissmeyer, V.
AU  - Wurst, W.
AU  - Krappmann, D.
C1  - 63658
C2  - 51503
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease.
JO  - Sci. Immunol.
VL  - 6
IS  - 65
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - Interleukin-17A- (IL-17A) and IL-17F-producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
AU  - Regen, T.*
AU  - Isaac, S.*
AU  - Amorim, A.*
AU  - Núñez, N.G.*
AU  - Hauptmann, J.*
AU  - Shanmugavadivu, A.*
AU  - Klein, M.*
AU  - Sankowski, R.*
AU  - Mufazalov, I.A.*
AU  - Yogev, N.*
AU  - Huppert, J.*
AU  - Wanke, F.*
AU  - Witting,M.
AU  - Grill, A.*
AU  - Gálvez, E.J.C.*
AU  - Nikolaev, A.*
AU  - Blanfeld, M.*
AU  - Prinz, I.*
AU  - Schmitt-Kopplin, P.
AU  - Strowig, T.*
AU  - Reinhardt, C.*
AU  - Prinz, M.*
AU  - Bopp, T.*
AU  - Becher, B.*
AU  - Ubeda, C.*
AU  - Waisman, A.*
C1  - 61341
C2  - 50170
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - IL-17 controls central nervous system autoimmunity through the intestinal microbiome.
JO  - Sci. Immunol.
VL  - 6
IS  - 56
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2470-9468
ER  - 

TY  - JOUR
AB  - Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [ house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13(+)CD4(+) T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary Lin(neg)CD45(+)CD90(+)IL-13(+) type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4(cre)IL-13 KO mice (lacking IL-13(+)CD4(+) T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13(+) ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13(+)CD4(+) T cells, whereas IL-13(+) ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4(cre)IL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13(+)CD4(+) T cells, rather than IL-13(+) ILCs or IL-33, are critical for inception of allergic AHR in early life.
AU  - Saglani, S.*
AU  - Gregory, L.G.*
AU  - Manghera, A.K.*
AU  - Branchett, W.J.*
AU  - Uwadiae, F.*
AU  - Entwistle, L.J.*
AU  - Oliver, R.A.*
AU  - Vasiliou, J.E.*
AU  - Sherburn, R.*
AU  - Lui, S.*
AU  - Puttur, F.*
AU  - Vöhringer, D.*
AU  - Walker, S.A.*
AU  - Buckley, J.*
AU  - Grychtol, R.*
AU  - Fainardi, V.*
AU  - Denney, L.*
AU  - Byrne, A.*
AU  - von Mutius, E.
AU  - Bush, A.*
AU  - Lloyd, C.M.*
C1  - 54250
C2  - 45454
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Inception of early-life allergen-induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells.
JO  - Sci. Immunol.
VL  - 3
IS  - 27
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 2470-9468
ER  -