Generation of pathogenic T(H)17 cells in the absence of TGF-ß signalling.
Nature
; 467(7318): 967-71, 2010 Oct 21.
Article
in En
| MEDLINE
| ID: mdl-20962846
ABSTRACT
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)-ß1 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-ß signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1ß effectively induced IL-17 production in naive precursors, independently of TGF-ß. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-ß1, 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-ß1 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Transforming Growth Factor beta
/
Th17 Cells
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nature
Year:
2010
Type:
Article
Affiliation country:
United States