Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Department of Biostatistics, College of Medicine, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610, USA.
Sci Adv. 2019 Aug 7;5(8):eaaw0480. doi: 10.1126/sciadv.aaw0480. eCollection 2019 Aug.
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.
调节性 T（T）细胞对于外周耐受至关重要，其生成和功能依赖于转录因子（TF）Foxp3。其他几个 TF 对于 T 细胞程序也至关重要。我们发现，仅在 T 细胞中缺乏 Bcl11b TF 的小鼠会发展为致命的自身免疫，并且 Bcl11b 缺陷型 T 细胞的功能严重改变。Bcl11b KO T 细胞在稳态、炎症和肿瘤条件下表现出功能标记物水平降低。Bcl11b 在稳态和炎症条件下控制着必需的 T 程序基因的表达。Bcl11b 在人和小鼠 T 细胞中与 Foxp3 结合，结合到 T 程序基因的基因组调节区域；在缺乏 Bcl11b 的情况下，这些基因的染色质可及性发生改变。此外，Bcl11b 限制了 T 细胞中的髓样细胞和 NK 细胞程序。我们的研究为 T 细胞程序和身份控制提供了新的机制见解，对于自身免疫和癌症的治疗具有重要意义。
