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

Abstract

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.