Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced T_reg differentiation via up-regulating Nr4a2

Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. While SRC1 inhibits the differentiation of regulatory T cells (T_regs) critical for establishing immune tolerance, we show here that SRC2 stimulates T_reg differentiation. SRC2 is dispensable for the development of thymic T_regs, whereas naive CD4⁺ T cells from mice deficient of SRC2 specific in T_regs (SRC2^fl/fl/Foxp3^YFP-Cre) display defective T_reg differentiation. Furthermore, the aged SRC2^fl/fl/Foxp3^YFP-Cre mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4⁺ T cells. SRC2^fl/fl/Foxp3^YFP-Cre mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced T_regs. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of Nr4a2, which then stimulates Foxp3 expression to promote T_reg differentiation. Members of SRC family coactivators thus play distinct roles in T_reg differentiation and are potential drug targets for controlling immune tolerance.