Early studies suggested that TIGIT indirectly suppresses immune responses via interacting with CD155 on DCs. TIGIT engages CD155 as a homodimer, where each TIGIT molecule binds one CD155 molecule, thus assembling into a heterotetramer with a TIGIT homodimeric core. TIGIT binding induces phosphorylation of the ITIM motif in the CD155 cytoplasmic tail resulting in recruitment of SHP-2 and phosphorylation of Erk. Overall, this leads to a decrease in IL-12p40 while increasing IL-10 production in DCs. TIGIT thus inhibits T cell responses indirectly by inducing tolerogenic DCs through the engagement of CD155.
Mechanism of TIGIT and CD155 Pathway
A few models have been proposed for how TIGIT mediates its inhibitory function. TIGIT has a higher affinity for CD155 than CD226. Thus, TIGIT can outcompete CD226 for binding to CD155, thereby disrupting CD226 co-stimulation and allowing TIGIT to deliver a cell-intrinsic inhibitory signal while also triggering a cell-extrinsic inhibitory signal via ligation of CD155. A second mechanism by which TIGIT can disrupt CD226 signaling has been proposed based on data obtained using fluorescence resonance energy transfer (FRET), which shows that TIGIT expression on T cells can interfere with the cis-homodimerization of CD226.
Fig.1 Mechanisms of TIGIT inhibition. (Dougall, 2017)
Researches of TIGIT and CD155 Pathway
Early studies showed that TIGIT could regulate T cell responses in a cell-extrinsic manner via engagement of CD155, which has its own ITIM motif in DCs. TIGIT homodimerization and interaction with CD155 in trans was required for tyrosine phosphorylation of the CD155 tail and recruitment of SHP-2, which inhibits Erk activation in DCs. The outcome is a shift in cytokine production from IL-12p40 production to IL-10. Thus, TIGIT-CD155 signaling dampens T-cell responses indirectly by promoting tolerogenic DC phenotype.
Although initial studies suggested that TIGIT engagement did not transfer signal into T cells directly, subsequent studies showed that TIGIT inhibited T cells in a cell-intrinsic manner. The cell-intrinsic inhibitory role for TIGIT is demonstrated by a recent study that compared melanoma cells expressing wildtype CD155 versus mutated CD155 that lacked the cytoplasmic tail. This study found that when T cells were cultured together with these melanoma cells, both wildtype and mutated CD155 were able to inhibit IFN-γ production by CD8+ T cells, indicating that TIGIT/CD155 ligation did not require signaling through CD155 to dampen T-cell responses. Moreover, stimulation of Treg with agonistic anti-TIGIT antibodies induces Treg effector molecules such as IL-10 and fgl2, further demonstrating a cell-intrinsic role for TIGIT.
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