Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells
Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells
复制标题
DOI：
10.1016/j.immuni.2015.11.009
复制
发表时间：
2016-01-19
期刊：
影响因子：
32.4
通讯作者：
Cua, Daniel J.
中科院分区：
文献类型：
--
作者：
Jain, Renu;Chen, Yi;Cua, Daniel J.
白细胞介素-23（IL-23）是辅助性T细胞17（Th 17）的致病性所需的促炎细胞因子，但控制这一过程的分子机制仍不清楚。我们确定了转录因子Blimp-1（Prdm 1）作为驱动Th 17细胞炎症功能的关键IL-23诱导因子。与导致T细胞发育缺陷和自发性自身免疫的Blimp-1的胸腺缺失相反，该转录因子的外周缺失导致Th 17活化减少和自身免疫性脑脊髓炎的严重程度降低。此外，在Th 17细胞中的全基因组占据和过表达研究显示，Blimp-1与转录因子ROR γ t、STAT-3和p300共定位于IL 23 r、IL 17 a/f和Csf 2细胞因子基因座，以增强其表达。Blimp-1还直接结合并抑制细胞因子位点II 2和Bcl 6。综上所述，我们的结果表明，Blimp-1是IL-23下游的一个重要转录因子，它与RORgt协同作用以激活Th 17炎症程序。
Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors ROR gamma t, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORgt to activate the Th17 inflammatory program.