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