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.