Bcl11b prevents fatal autoimmunity by promoting T cell program and constraining innate lineages in T cells.

Regulatory T (T) cells are essential for peripheral tolerance and rely on the transcription factor (TF) Foxp3 for their generation and function. Several other TFs are critical for the T cell program. We found that mice deficient in Bcl11b TF solely in T cells developed fatal autoimmunity, and Bcl11b-deficient T cells had severely altered function. Bcl11b KO T cells showed decreased functional marker levels in homeostatic conditions, inflammation, and tumors. Bcl11b controlled expression of essential T program genes at steady state and in inflammation. Bcl11b bound to genomic regulatory regions of T program genes in both human and mouse T cells, overlapping with Foxp3 binding; these genes showed altered chromatin accessibility in the absence of Bcl11b. Additionally, Bcl11b restrained myeloid and NK cell programs in T cells. Our study provides new mechanistic insights on the T cell program and identity control, with major implications for therapies in autoimmunity and cancer.