IL-36γ signaling controls the induced regulatory T cell-Th9 cell balance via NFκB activation and STAT transcription factors.
Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4+T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from Th cell-driven intestinal inflammation and exhibited increased colonic Tregcells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the Treg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
A
A
Harusato
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
H
H
Abo
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
V L
VL
Ngo
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
S W
SW
Yi
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
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K
Mitsutake
Department of Neurosurgery, Emory University, Atlanta, Georgia, USA.
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S
Osuka
Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
J E
JE
Kohlmeier
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
J D
JD
Li
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
A T
AT
Gewirtz
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
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A
Nusrat
Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
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TL
Denning
D000818:Animals; D001572:Benzofurans; D002454:Cell Differentiation; D003093:Colitis, Ulcerative / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D016906:Interleukin-9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
D001572:Benzofurans; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D016906:Interleukin-9; D053594:Myeloid Differentiation Factor 88; D011804:Quinolines; D017472:Receptors, Interleukin-1; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; D051996:Transcription Factor RelA; C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; C498833:Foxp3 protein, mouse; C498144:Rela protein, mouse; C569500:Il1rl2 protein, mouse