Department of Medicine, Division of Pulmonary Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32610, USA.
Nat Commun. 2018 Apr 26;9(1):1679. doi: 10.1038/s41467-018-04111-0.
During helminth infection and allergic asthma, naive CD4 T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.
在寄生虫感染和过敏性哮喘中，幼稚 CD4 T 细胞分化为产生细胞因子的辅助性 T 细胞 2（Th2），从而清除感染或诱导与哮喘相关的病理。体内调节 Th2 分化的机制仍知之甚少。本研究报告称，在成熟 T 细胞中缺乏 Bcl11b 的小鼠在寄生虫感染和过敏性哮喘期间产生 Th2 反应的能力减弱，表现为 Th2 细胞因子和 Gata3 减少，Runx3 增加。本研究提供了证据表明，Bcl11b 需要维持 Th2 细胞因子启动子和基因座控制区的染色质可及性，并结合 Il4 HS IV 沉默子，降低其可及性。Bcl11b 还结合 Gata3 内含子和下游非编码位点，维持 Gata3 的表达。此外，Bcl11b 结合并失活 Runx3 基因座上的上游增强子，限制 Runx3 的表达及其在 Il4 HS IV 沉默子上的作用。因此，本研究结果确立了 Bcl11b 在体内 Th2 程序调控环中的新作用。
