The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function
The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function
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DOI：
10.1016/j.ccell.2014.10.018
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发表时间：
2014-12-08
期刊：
影响因子：
50.3
通讯作者：
Grogan, Jane L.
中科院分区：
文献类型：
--
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
肿瘤构成高度抑制性的微环境，其中浸润的T细胞被PD-1等抑制性受体“耗尽”。在这里，我们确定TIGIT作为一种共抑制受体，严重限制抗肿瘤和其他CD8(+) T细胞依赖的慢性免疫反应。TIGIT在人类和小鼠肿瘤浸润T细胞上高表达，在癌症和慢性病毒感染模型中，抗体共阻断TIGIT和PD-L1协同特异性增强CD8(+) T细胞效应功能，分别导致显著的肿瘤和病毒清除。这种作用通过阻断TIGIT的互补共刺激受体CD226而被消除，CD226在与TIGIT直接顺式相互作用时二聚体被破坏。这些结果确定了TIGIT在抑制慢性CD8(+) T细胞依赖性反应中的关键作用。
Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblock-ade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.