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. 2024 Oct 1;56(10):2113–2126. doi: 10.1038/s12276-024-01317-9

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — TIGIT, CD226, CD96, and CD112R are expressed mainly on T cells and NK cells. The ligands PVR, Nectin-1, Nectin-2, Nectin-3 and Nectin-4 are expressed on tumor cells and antigen-presenting cells (APCs). TIGIT binds PVR, Nectin-2, Nectin-3, and Nectin-4, while CD226 binds PVR and Nectin-2, and CD96 binds PVR and Nectin-1. CD226 competes with TIGIT and CD96 for PVR binding and with CD112R for Nectin-2 binding. The cytoplasmic tails of TIGIT, CD96, CD112R, and PVR contain ITIM motifs that initiate inhibitory signals, while TIGIT also features an ITT-like motif. CD226 binds PVR to transmit positive signals and associates with LFA-1. The signaling outcome of CD96 binding to CD155 in human T cells is still unclear. CD112R binds CD112 to deliver an inhibitory signal via its ITIM. Two-sided arrows indicate receptor‒ligand interactions, and their size is proportional to the reported affinities. Keywords: APCs (antigen-presenting cells), ITIM (immunoreceptor tyrosine-based inhibitory motif), ITT (Ig tail-tyrosine), NK cells (natural killer cells), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains).