Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and Abu Haidar Neuroscience Institute, American University of Beirut, Beirut 1107-2020, Lebanon
J Immunol. 2014 Jul 1;193(1):198-207. doi: 10.4049/jimmunol.1303184. Epub 2014 May 30.
The transcriptional repressor B cell lymphoma 6 (BCL6) is required for the development of Th follicular cells, and it has been shown to suppress Th2 cell differentiation. We demonstrate that BCL6 is a key regulator of Th9 cell development. BCL6 expression is transiently downregulated in polarized Th9 cells, and forced expression of BCL6 in Th9 cells impairs Th9 cell differentiation. In contrast, BCL6 knockdown upregulated IL-9 production in Th9 cells. The function of BCL6 in Th9 cells is under the control of IL-2/JAK3/STAT5 signaling pathway. Using chromatin immunoprecipitation, we show that, in Th9 cells, BCL6 and STAT5 bind to adjacent motifs in the Il9 promoter. Furthermore, we found that STAT5 binding was associated with the abundance of a permissive histone mark at the Il9 promoter, whereas under conditions in which BCL6 binding was predominant, a repressive histone mark was prevalent. The effects of STAT5 and BCL6 on IL-9 transcription were further demonstrated using an IL-9 luciferase reporter assay in which BCL6 repressed STAT5-mediated Il9 transactivation. In experimental autoimmune encephalomyelitis, forced expression of BCL6 in myelin oligodendrocyte glycoprotein35-55-specific Th9 cells resulted in decreased IL-9 production and induction of IFN-γ, causing an exacerbation of the clinical disease. Our findings demonstrate a novel role of BCL6 in the regulation of Th9 cell development and their encephalitogenicity.
转录抑制因子 B 细胞淋巴瘤 6（BCL6）是 Th 滤泡细胞发育所必需的，并且已被证明可抑制 Th2 细胞分化。我们证明 BCL6 是 Th9 细胞发育的关键调节因子。BCL6 在极化的 Th9 细胞中短暂下调表达，而在 Th9 细胞中强制表达 BCL6 会损害 Th9 细胞分化。相反，BCL6 敲低可上调 Th9 细胞中的 IL-9 产生。BCL6 在 Th9 细胞中的功能受 IL-2/JAK3/STAT5 信号通路的控制。通过染色质免疫沉淀，我们表明在 Th9 细胞中，BCL6 和 STAT5 结合到 Il9 启动子的相邻基序上。此外，我们发现 STAT5 结合与 Il9 启动子上允许性组蛋白标记的丰度相关，而在 BCL6 结合占优势的条件下，存在抑制性组蛋白标记。通过在 IL-9 荧光素酶报告基因测定中使用 STAT5 和 BCL6 对 IL-9 转录的影响进一步证明了这一点，其中 BCL6 抑制 STAT5 介导的 Il9 反式激活。在实验性自身免疫性脑脊髓炎中，髓鞘少突胶质细胞糖蛋白 35-55 特异性 Th9 细胞中 BCL6 的强制表达导致 IL-9 产生减少和 IFN-γ的诱导，从而导致临床疾病加重。我们的研究结果表明 BCL6 在调节 Th9 细胞发育及其致脑炎作用方面具有新的作用。
