Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced Treg 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 IFN gamma-producing CD4+ T cells. SRC2fl/fl/Foxp3YFP-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.