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.