T-bet and eomesodermin play critical roles in directing T cell differentiation to Th1 versus Th17.
Th1 and Th17 cells are crucial in immune regulation and autoimmune disease development. By adding Stat6 deficiency to T-bet deficiency, and thus negating effects from elevated levels of IL-4/Stat6/GATA3 Th2 signals in T-bet-deficient cells, we investigated the signals important for Th1 and Th17 cell differentiation and their role in colitis development. The data reveal that Eomesodermin compensates T-bet deficiency for IFN-gamma and Th1 development. However, without T-bet, IFN-gamma production and Th1 differentiation are susceptible to inhibition by IL-6 and TGFbeta. As a result, Th17 development is strongly favored, the threshold for TGFbeta requirement is lowered, and IL-6 drives Th17 differentiation, elucidating a critical role for T-bet in directing T cell differentiation to Th1 vs Th17. In contrast to IL-6 plus TGFbeta-driven Th17, IL-6-driven Th17 cells do not express IL-10 and they induce a more intense colitis. Naive CD4 T cells deficient in Stat6 and T-bet also induce a Th17-dominant colitis development in vivo. Our data provide new insights into the choice between Th1 and Th17 development and their roles in autoimmunity.
Yang
Yu
Y
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Xu
Jiangnan
J
Niu
Yanyan
Y
Bromberg
Jonathan S
JS
Ding
Yaozhong
Y
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D050800:STAT6 Transcription Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000098815:T-bet Transcription Factor
C491198:Eomes protein, mouse; D020381:Interleukin-17; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma