T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (RORgamma) was shown to regulate Th17 differentiation; RORgamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, RORalpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of RORalpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. RORalpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, RORalpha and RORgamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in RORalpha and RORgamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, RORalpha and RORgamma.
T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORalpha and RORgamma. Publishing Authors By Initials
