Fyn Promotes Th17 Differentiation by Regulating the Kinetics of RORγt and Foxp3 Expression

Th17 cells constitute a proinflammatory CD4 + T cell subset that is important for microbial clearance, but also are implicated as propagators of various autoimmune pathologies. Evidence suggests that Th17 cells share common progenitors with immunosuppressive CD4 + inducible regulatory T cells (T REG ) and that the developmental pathways of these two subsets are reciprocally regulated. In this study, we show evidence that the Src family tyrosine kinase Fyn helps regulate this Th17/T REG balance. When placed under Th17-skewing conditions, CD4 + T cells from fyn −/− mice had decreased levels of IL-17, but increased expression of the T REG transcription factor Foxp3. The defect in IL-17 expression occurred independently of the ectopic Foxp3 expression and correlated with a delay in retinoic acid-related orphan receptor γt upregulation and an inability to maintain normal STAT3 activation. Fyn-deficient Th17 cells also exhibited delayed upregulation of Il23r , Il21 , Rora , and Irf4 , as well as aberrant expression of Socs3 , suggesting that Fyn may function upstream of a variety of molecular pathways that contribute to Th17 polarization. The fyn −/− mice had fewer IL-17 + CD4 + T cells in the large intestinal lamina propria compared with littermate controls. Furthermore, after transfer of either wild-type or fyn −/− naive CD4 + T cells into Rag1 −/− hosts, recipients receiving fyn −/− cells had fewer IL-17–producing T cells, indicating that Fyn may also regulate Th17 differentiation in vivo. These results identify Fyn as a possible novel regulator of the developmental balance between the Th17 cell and T REG subsets.