TIGIT (T cell Immunoreceptor with Ig and ITIM domains), also called Vstm3 (V‑set and transmembrane domain‑containing 3), Vsig9 (V‑set and Ig domain-containing 9) and WUCAM (Washington University cell adhesion molecule) is a 30‑34 kDa type I transmembrane protein that is a member of the CD28 family within the Ig superfamily of proteins (1‑4). Mouse TIGIT cDNA encodes 241 amino acids (aa) including a 26 aa signal sequence, a 115 aa extracellular region with a V‑type Ig-like domain and one potential N‑glycosylation site, a 21 aa transmembrane sequence, and a 79 aa cytoplasmic domain with an ITIM motif (5). A 249 aa variant contains inserted aa after aa 21, 131 and 164 (6). Within the ECD, mouse TIGIT shares only 59‑70% aa sequence identity with human, porcine, canine, equine and bovine TIGIT. TIGIT is expressed on NK cells and subsets of activated, memory and regulatory T cells, and particularly on follicular helper T cells within secondary lymphoid organs (1, 2, 7‑9). It binds to CD155/PVR/Necl‑5 and Nectin-2/CD112/PVRL2 that appear on dendritic cells (DC) and endothelium (1‑3, 8). Binding of TIGIT by DC induces IL‑10 release and inhibits IL‑12 production (2). Ligation of TIGIT on T cells down‑regulates TCR-mediated activation and subsequent proliferation, while NK cell TIGIT ligation blocks NK cell cytotoxicity (7‑9). Through CD155 and Nectin-2, which also interact with DNAM-1/CD226 and CD96/Tactile, TIGIT is part of an interacting network of Ig superfamily members that may augment or oppose each other (3, 4, 7, 8). In particular, TIGIT binding to CD155 can antagonize the effects of DNAM‑1 (7, 8). Soluble TIGIT is able to compete with DNAM‑1 for CD155 binding and attenuates T cell responses, while mice lacking TIGIT show increased T cell responses and susceptibility to autoimmune challenges (2, 3, 9, 10).
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