SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Regulatory T cells (T_reg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of T_reg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1^-/- Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2^-/- mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1^-/- T_reg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ^-/-Socs1^-/- T_reg cells, the restriction of IFN-γ-STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ^-/-Socs1^-/- Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ^-/-Socs1^+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2^-/- mice. In vitro experiments suggested that cytokines produced by Socs1^-/- T_reg cells and Ifnγ^-/-Socs1^-/- T_reg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in T_reg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.