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.
|Co-inhibitory immune checkpoint pathways||Co-stimulatory immune checkpoint pathways|
|PD1 & PD-L1 immune checkpoint pathway||CD40 & CD40L immune checkpoint pathway|
|CTLA-4 & CD80 (CD86) immune checkpoint pathway||OX40 & OX40L immune checkpoint pathway|
|B7-H3 / CD276 immune checkpoint pathway||HVEM & LIGHT immune checkpoint pathway|
|B7-H4 / B7S1 / B7x immune checkpoint pathway||CD28 & CD80 (CD86) immune checkpoint pathway|
|HVEM & BTLA immune checkpoint pathway||GITR & GITR Ligand immune checkpoint pathway|
|HVEM & CD160 immune checkpoint pathway||CD27 & CD70 immune checkpoint pathway|
|LAG3 / CD223 / Lymphocyte activation gene 3 immune checkpoint pathway||4-1BB & 4-1BBL immune checkpoint pathway|
|Galectin-9 & TIM-3 immune checkpoint pathway||ICOS & ICOS Ligand immune checkpoint pathway|
|Indoleamine 2,3-dioxygenase/IDO immune checkpoint pathway||CD266 & CD155 immune checkpoint pathway|
|VISTA / B7-H5 / GI24 immune checkpoint pathway|
|CEACAM1 / CD66a immune checkpoint pathway|
|SIRP alpha & CD47 immune checkpoint pathway|
|2B4 & CD48 immune checkpoint pathway|