The molecule TIGIT / VSTM3 was identified initially in a genome-wide screen for molecules that (a) are expressed by immune cells and (b) contain the well-defined inhibitory ITIM motif, which is known to mediate inactivating signals in a variety of immune cells. TIGIT / VSTM3 is expressed normally by activated T cells, regulatory T cells (Treg), and natural killer (NK) cells. The poliovirus receptor (CD155 / PVR) and Nectin-2 (CD112) have been identified as relevant ligands. TIGIT / VSTM3 competes with the molecules CD226 and CD96 for binding to CD155 / PVR and CD112, respectively, but among all respective receptor-ligand combinations, TIGIT / VSTM3 exhibits the strongest affinity for CD155 / PVR. Interestingly, the other known receptor for CD155 / PVR, CD226, conveys activating signals into T cells, whereas TIGIT / VSTM3 clearly has suppressive activity. This competition of an inhibitory receptor (TIGIT / VSTM3) and a stimulatory receptor (CD226) for one ligand (CD155) is reminiscent of the CTLA4-CD28-B7 axis. This similarity of the TIGIT & CD155 immune checkpoint pathway to the already known suppressive CTLA4-CD28 pathway, as well as the expression of TIGIT by exhausted T cells and by Treg, prompted investigators to speculate that the TIGIT / VSTM3-CD155 axis in tumors might serve as a checkpoint for tumor growth.
Karsten Mahnke et al. TIGIT-CD155 Interactions in Melanoma: A Novel Co-Inhibitory Pathway with Potential for Clinical Intervention. Journal of Investigative Dermatology. 2016; 136: 9–11.