TIGIT predominantly regulates the immune response via regulatory T cells
TIGIT predominantly regulates the immune response via regulatory T cells
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DOI：
10.1172/jci81187
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发表时间：
2015-11-01
影响因子：
15.9
通讯作者：
Anderson, Ana C.
中科院分区：
文献类型：
--
作者：
Kurtulus, Sema;Sakuishi, Kaori;Anderson, Ana C.
共抑制受体对于维持免疫稳态至关重要。效应T细胞上的这些受体的上调终止T细胞应答，而它们在T细胞上的表达促进它们的抑制功能。了解效应T细胞和T细胞中共抑制受体的功能至关重要，因为靶向共抑制受体的疗法目前处于癌症和其他慢性疾病治疗策略的最前沿。T细胞IG和ITIM结构域（TIGIT）是最近鉴定的共抑制受体，其在多种淋巴细胞表面上发现，并且其在免疫调节中的作用刚刚开始被阐明。我们在不同的鼠癌症模型中检查了TIGIT介导的免疫调节，并确定TIGIT标记肿瘤组织中CD8（+）T细胞以及具有高度活性和抑制性表型的肿瘤组织T细胞中功能最失调的亚群。我们证明了TIGIT信号转导在T细胞中指导它们的表型，并且TIGIT主要通过T细胞而不是CD8（+）T细胞抑制抗肿瘤免疫。此外，TIGIT（+）TIGIT上调肿瘤组织中共抑制受体TIM-3的表达，并且TIM-3和TIGIT协同抑制抗肿瘤免疫应答。我们的研究结果为TIGIT如何在慢性疾病环境中调节免疫反应提供了机制性见解。
Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8(+)T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8(+)T cells. Moreover, TIGIT(+) Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.