Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced T<sub>reg</sub> differentiation via up-regulating Nr4a2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35704583.
- Also identified by DOI 10.1126/sciadv.abn7662 and PMC identifier 9200286.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sub>regs</sub>) critical for establishing immune tolerance, we show here that SRC2 stimulates T<sub>reg</sub> differentiation. SRC2 is dispensable for the development of thymic T<sub>regs</sub>, whereas naive CD4<sup>+</sup> T cells from mice deficient of SRC2 specific in T<sub>regs</sub> (<i>SRC2<sup>fl/fl</sup>/Foxp3<sup>YFP-Cre</sup></i>) display defective T<sub>reg</sub> differentiation. Furthermore, the aged <i>SRC2<sup>fl/fl</sup>/Foxp3<sup>YFP-Cre</sup></i> mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4<sup>+</sup> T cells. <i>SRC2<sup>fl/fl</sup>/Foxp3<sup>YFP-Cre</sup></i> mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced T<sub>regs</sub>. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of <i>Nr4a2</i>, which then stimulates Foxp3 expression to promote T<sub>reg</sub> differentiation. Members of SRC family coactivators thus play distinct roles in T<sub>reg</sub> differentiation and are potential drug targets for controlling immune tolerance.