TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.
TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.
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DOI：
10.1038/s41467-023-40755-3
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发表时间：
2023-08-18
影响因子：
16.6
通讯作者：
Davis, Daniel M.
中科院分区：
文献类型：
--
作者：
Worboys, Jonathan D.;Vowell, Katherine N.;Hare, Roseanna K.;Ambrose, Ashley R.;Bertuzzi, Margherita;Conner, Michael A.;Patel, Florence P.;Zammit, William H.;Gali-Moya, Judit;Hazime, Khodor S.;Jones, Katherine L.;Rey, Camille;Jonjic, Stipan;Rovis, Tihana Lenac;Tannahill, Gillian M.;Cruz De Matos, Gabriela Dos Santos;Waight, Jeremy D.;Davis, Daniel M.
TIGIT是一种表达在淋巴细胞上的抑制性受体，可以通过顺式相互作用或通过共享配体的竞争阻止CD 226共刺激来抑制T细胞。TIGIT是否直接在T细胞中递送细胞内在抑制信号仍不清楚。在这里，我们通过分析来自匹配的人肿瘤和外周血样品的淋巴细胞显示，TIGIT和⑶ 226共表达在肿瘤浸润淋巴细胞上是罕见的。使用超分辨率显微镜和其他技术，我们证明了与CD155的连接导致TIGIT重组成致密的纳米簇，这些纳米簇与免疫突触处富含T细胞受体（TCR）的簇合并。在功能上，这以依赖于TIGIT的细胞内ITT样信号传导基序的方式减少细胞因子分泌。因此，我们提供了TIGIT直接抑制淋巴细胞活化的证据，其独立于CD226起作用，需要邻近TCR的细胞内信号传导。在TIGIT表达细胞通常不共表达⑶ 226的肿瘤亚组内，这可能是主要的作用机制。CD226在活化期间向T细胞受体提供共刺激信号，并且TIGIT被认为通过竞争CD226配体CD155来抑制该过程。在这里，作者表明配体结合通过TIGIT诱导致密纳米簇形成，TIGIT启动内在的、CD226非依赖性抑制信号，接近T细胞受体信号传导。
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action. CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
7.3
作者：
Bálint Š;Lopes FB;Davis DM
通讯作者：
Davis DM
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.
LAG3与TCR-CD3复合物相关，并通过驱动共受体LCK解离来抑制信号传导。
影响因子：
30.5
作者：
Guy, Clifford;Mitrea, Diana M.;Chou, Po-Chien;Temirov, Jamshid;Vignali, Kate M.;Liu, Xueyan;Zhang, Hui;Kriwacki, Richard;Bruchez, Marcel P.;Watkins, Simon C.;Workman, Creg J.;Vignali, Dario A. A.
通讯作者：
Vignali, Dario A. A.
影响因子：
7
作者：
Kinoshita, E;Kinoshita-Kikuta, E;Koike, T
通讯作者：
Koike, T