Yu Di, Rao Sudha, Tsai Louis M, Lee Sau K, He Yiqing, Sutcliffe Elissa L, Srivastava Monika, Linterman Michelle, Zheng Lei, Simpson Nicholas, Ellyard Julia I, Parish Ian A, Ma Cindy S, Li Qi-Jing, Parish Christopher R, Mackay Charles R, Vinuesa Carola G
Immunology and inflammation, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Immunity. 2009 Sep 18;31(3):457-68. doi: 10.1016/j.immuni.2009.07.002. Epub 2009 Jul 23.
Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
滤泡辅助性T（Tfh）细胞为生发中心B细胞提供选择信号，这对长期抗体应答至关重要。高CXCR5表达和低CCR7表达有助于它们归巢至B细胞滤泡，并将它们与辅助性T细胞1（Th1）、辅助性T细胞2（Th2）及辅助性T细胞17（Th17）区分开来。在此，我们发现Bcl-6指导Tfh细胞分化：Bcl-6缺陷型T细胞无法发育为Tfh细胞，且无法维持生发中心应答，而在CD4(+) T细胞中强制表达Bcl-6可促进Tfh细胞标志性分子CXCR5、CXCR4和PD-1的表达。Bcl-6与Th1和Th17细胞转录调节因子T-bet和RORγt的启动子结合，并抑制IFN-γ和IL-17的产生。Bcl-6还抑制了许多预测可控制Tfh细胞特征的微小RNA（miRNA）的表达，包括抑制CXCR5表达的miR-17-92。因此，Bcl-6通过联合抑制miRNA和转录因子，正向指导Tfh细胞分化。
