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

Regulatory T (T-reg) 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-reg cell program. We found that mice deficient in Bcl11b TF solely in T-reg cells developed fatal autoimmunity, and Bcl11b-deficient T-reg cells had severely altered function. Bcl11b KO T-reg cells showed decreased functional marker levels in homeostatic conditions, inflammation, and tumors. Bcl11b controlled expression of essential T-reg program genes at steady state and in inflammation. Bcl11b bound to genomic regulatory regions of T-reg program genes in both human and mouse T-reg 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-reg cells. Our study provides new mechanistic insights on the T-reg cell program and identity control, with major implications for therapies in autoimmunity and cancer.