Journal Article

Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling

McGeachy, Mandy J, Wei, Lai, Grainger, John R, Chen, Wanjun, Laurence, Arian, Ramos, Haydeé L, Yang, Xiang-Ping, Cua, Daniel J, Watford, Wendy T, Shevach, Ethan M, Konkel, Joanne E, Bouladoux, Nicolas, Kanno, Yuka, O'Shea, John J, Chen, Qian, Sun, Hong-Wei, Eberl, Gérard, Ghoreschi, Kamran, Davidson, Todd S, Tato, Cristina M, Belkaid, Yasmine

2010

نظرة عامة

CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet(+)RORγt(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

• موضوع: Animals / Autoimmune Diseases - immunology / Autoimmune Diseases - pathology / Autoimmunity - immunology / Cell Differentiation - drug effects / Central Nervous System - pathology / Inflammation / Interleukin-10 / Interleukin-17 - metabolism / Interleukin-1beta - immunology / Interleukin-22 / Interleukin-23 - immunology / Interleukin-23 - pharmacology / Interleukin-6 - immunology / Interleukin-9 / Interleukins - biosynthesis / Mice / Mice, Inbred C57BL / Mucous Membrane - cytology / Mucous Membrane - immunology / Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism / Receptors, Interleukin - metabolism / Signal Transduction / Th17 Cells - drug effects / Th17 Cells - metabolism / Th17 Cells - pathology / Transforming Growth Factor beta