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 (TREG) 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 gamma t 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. The Journal of Immunology, 2012, 188: 5247-5256.