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.