Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.
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.
Ghoreschi
Kamran
K
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ghoreschik@mail.nih.gov
Laurence
Arian
A
Yang
Xiang-Ping
XP
Tato
Cristina M
CM
McGeachy
Mandy J
MJ
Konkel
Joanne E
JE
Ramos
Haydeé L
HL
Wei
Lai
L
Davidson
Todd S
TS
Bouladoux
Nicolas
N
Grainger
John R
JR
Chen
Qian
Q
Kanno
Yuka
Y
Watford
Wendy T
WT
Sun
Hong-Wei
HW
Eberl
Gérard
G
Shevach
Ethan M
EM
Belkaid
Yasmine
Y
Cua
Daniel J
DJ
Chen
Wanjun
W
O'Shea
John J
JJ
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002490:Central Nervous System / Q000473:pathology; D007249:Inflammation; D016753:Interleukin-10; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology; D016906:Interleukin-9; D007378:Interleukins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta; D000097043:Interleukin-22
D016753:Interleukin-10; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D016906:Interleukin-9; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018123:Receptors, Interleukin; D016212:Transforming Growth Factor beta; D000097043:Interleukin-22; C528688:interleukin-23 receptor, mouse