When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function
When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function
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DOI：
10.1182/blood-2010-02-268169
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发表时间：
2010-11-04
期刊：
影响因子：
20.3
通讯作者：
Davila, Eduardo
中科院分区：
文献类型：
--
作者：
Geng, Degui;Zheng, Liqin;Davila, Eduardo
新出现的报告显示，激活CD8 T淋巴细胞中的Toll样受体2（TLR2）-MyD88信号可增强细胞因子的产生和细胞毒性；然而，该信号通路仍未明确。在本研究中，我们检测了这一过程所涉及的生理意义和分子机制。我们发现TLR2与T细胞受体转基因CD8 OT - 1 T细胞结合会增加T - bet转录因子水平，从而在体内和体外提高效应分子的转录和蛋白质水平。相比之下，TLR2激动剂不能共刺激TLR2（-/-）OT - 1或MyD88（-/-）OT - 1 T细胞。TLR2 - MyD88激活的T细胞中T - bet水平升高是由于雷帕霉素靶蛋白（mTOR）通路激活增强导致生物合成增加的结果。抑制T细胞中的mTOR、Akt或蛋白激酶C可消除TLR2激动剂的共刺激作用。在体内，激活T细胞中的TLR2 - MyD88信号可提高效应分子水平，并增强对单核细胞增生李斯特菌 - 卵清蛋白的清除。这些结果有助于确定一种以Akt和蛋白激酶C依赖的方式连接TLR - MyD88和mTOR通路的信号通路。这些结果凸显了MyD88信号在T细胞激活和细胞毒性中的关键作用。此外，这些发现为通过靶向T细胞内的TLR - MyD88信号来提高疫苗和基于T细胞的免疫疗法的疗效提供了机会。（《血液》2010年；116(18):3494 - 3504）
Emerging reports reveal that activating Toll-like receptor-2 (TLR2)-MyD88 signals in CD8 T lymphocytes enhances cytokine production and cytotoxicity; however, the signaling pathway remains undefined. In the present study, we examined the physiologic significance and molecular mechanisms involved in this process. We found that TLR2 engagement on T-cell receptor transgenic CD8 OT-1 T cells increased T-bet transcription factor levels consequently, augmenting effector transcript and protein levels both in vivo and in vitro. In contrast, TLR2 agonist did not costimulate TLR2(-/-) OT-1 or MyD88(-/-) OT-1 T cells. Elevated T-bet levels in TLR2-MyD88-activated T cells was a consequence of increased biosynthesis resulting from the enhanced activation of the mammalian target of the rapamycin (mTOR) pathway. Inhibiting mTOR, Akt, or protein kinase C in T cells abolished the costimulatory effects of the TLR2 agonist. In vivo, activating TLR2-MyD88 signals in T cells increased effector-molecule levels and enhanced the clearance of Listeria monocytogenes-Ova. These results help define a signaling pathway linking the TLR-MyD88 and mTOR pathway in an Akt- and protein kinase C-dependent manner. These results highlight a critical role for MyD88 signaling in T-cell activation and cytotoxicity. Furthermore, these findings offer the opportunity for improving the efficacy of vaccines and T cell-based immunotherapies by targeting TLR-MyD88 signaling within T cells. (Blood. 2010;116(18):3494-3504)