Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
GlaxoSmithKline, Collegeville, PA, USA.
Nat Commun. 2023 Aug 18;14(1):5016. doi: 10.1038/s41467-023-40755-3.
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.
TIGIT 是一种在淋巴细胞上表达的抑制性受体，可通过 cis 相互作用或通过共享配体的竞争来阻止 CD226 共刺激，从而抑制 T 细胞。TIGIT 是否直接在 T 细胞中传递细胞内抑制信号尚不清楚。在这里，我们通过分析来自配对的人类肿瘤和外周血样本的淋巴细胞，表明 TIGIT 和 CD226 的共表达在肿瘤浸润淋巴细胞上很少见。通过超分辨率显微镜和其他技术，我们证明与 CD155 的连接导致 TIGIT 重新排列成密集的纳米簇，这些纳米簇与 TCR 丰富的簇在免疫突触处融合。在功能上，这以依赖于 TIGIT 的 ITT 样信号基序的细胞内信号的方式减少细胞因子的分泌。因此，我们提供的证据表明 TIGIT 直接抑制淋巴细胞的激活，独立于 CD226 起作用，需要靠近 TCR 的细胞内信号。在 TIGIT 表达细胞通常不共同表达 CD226 的肿瘤亚群中，这可能是主要的作用机制。
