Toll-like receptor 2 induces pathogenicity in Th17 cells and reveals a role for IPCEF in regulating Th17 cell migration.
Toll-like receptor 2 induces pathogenicity in Th17 cells and reveals a role for IPCEF in regulating Th17 cell migration.
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DOI：
10.1016/j.celrep.2021.109303
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发表时间：
2021-06-29
期刊：
影响因子：
8.8
通讯作者：
Reynolds JM
中科院分区：
文献类型：
--
作者：
Marks KE;Flaherty S;Patterson KM;Stratton M;Martinez GJ;Reynolds JM
致病性Th17细胞在自身免疫性疾病中驱动炎症，然而Th17细胞致病性背后的分子编程仍未充分了解。toll样受体2 （TLR2）的激活增加了Th17细胞的炎症潜能，但关于TLR2信号传导在Th17细胞中的机制结果知之甚少。在这里，我们证明了TLR2在诱导Th17细胞的致病性和增加迁移能力方面与IL-23相当。我们对通过TLR2途径刺激的Th17细胞进行了RNA测序，发现与Th17遗传程序相关的几个基因以及先前与致病性Th17细胞无关的基因（包括Ipcef1）的差异表达。Ipcef1在Th17细胞中的强制表达消除了tlr2依赖性迁移能力的增加，严重损害了Th17细胞诱导实验性自身免疫性脑脊髓炎的能力。本研究确立了TLR2信号通路在诱导Th17细胞致病性和驱动自身免疫性炎症中的重要性。Marks等人证明了TLR2在驱动炎性T细胞功能中的重要作用。他们还揭示IPCEF是TLR2信号的靶标，IPCEF的表达抑制自身免疫性炎症模型中的致病性T细胞迁移。
Pathogenic Th17 cells drive inflammation in autoimmune disease, yet the molecular programming underlying Th17 cell pathogenicity remains insufficiently understood. Activation of Toll-like receptor 2 (TLR2) increases Th17 cell inflammatory potential, but little is known regarding the mechanistic outcomes of TLR2 signaling in Th17 cells. Here, we demonstrate that TLR2 is comparable to IL-23 in inducing pathogenicity and increasing the migratory capacity of Th17 cells. We perform RNA sequencing of Th17 cells stimulated though the TLR2 pathway and find differential expression of several genes linked with the Th17 genetic program as well as genes not previously associated with pathogenic Th17 cells, including Ipcef1. Enforced expression of Ipcef1 in Th17 cells abolishes the TLR2-dependent increases in migratory capacity and severely impairs the ability of Th17 cells to induce experimental autoimmune encephalomyelitis. This study establishes the importance of the TLR2 signaling pathway in inducing Th17 cell pathogenicity and driving autoimmune inflammation. Marks et al. demonstrate an important role for TLR2 in driving inflammatory T cell function. They also reveal that IPCEF is a target for TLR2 signaling and that IPCEF expression inhibits pathogenic T cell migration in a model of autoimmune inflammation.
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