Contribution Of Inhibitory Receptor TIGIT To NK Cell Education

Engagement of self-MHC molecules via their specific inhibitory receptors triggers Natural killer(NK)cell education,resulting in functional maturation and allowing NK cells to sense missing-self.However,several lines of evidence have revealed that,under certain conditions,the acquisition of NK cell functional maturation cannot be explained by MHC-I-dependent NK cell education.NK cells also express a wide variety of inhibitory receptors for non-MHC-I ligands.Subsequent studies on SLAMF6 and NKR-P1B receptors have provided some clues that these inhibitory receptors enhance NK cell effector function under certain circumstances.It remains to be confirmed whether interactions between non-MHC-specific inhibitory receptors and their cognate host ligands are able to regulate NK cell education.Normal healthy cells express CD 155.a non-MHC self-ligand,which can be recognized by inhibitory receptor TIGIT.In this manuscript,we showed that CD 155 acted as a non-MHC-I self marker and loss of CD 155 expression on splenocytes led to their rejection by NK cells in a TIGIT-dependent manner,thus confirming the role of TIGIT in mediating MHC-I-independent missing-self recognition by NK cells.We also found that in normal hosts,TIGIT+ NK cells exerted enhanced functional activity against various stimuli,including targets that lacked expression of(missing)self-CD155 ligand.In CD155-deficient hosts,however,TIGIT+ NK cells exhibited functional impairment,whereas TIGIT-NK cells remained unaffected,indicating that the engagement of TIGIT receptor by host CD155 molecule contributed to NK cell functional maturation.Furthermore,through mouse models of germline deletion and NK cell-specific deletion of TIGIT,we showed that TIGIT deficiency led to loss of NK cell-mediated missing-self recognition of CD 155-targets such as allogenic splenocytes and tumor cells,in an MHC-I-independent and CD226-unrelated manner.Therefore,like MHC-I-specific inhibitory receptors,TIGIT also enhanced NK cell responsiveness by a process akin to "NK cell education",representing a novel MHC-I-independent mechanism for NK cell tolerance and activation.Elucidating MHC-independent NK cell education allows a deeper understanding of NK cells to distinguish self and non-self and in turn potentiates clinical significance.