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Engagement of MHC class I molecules via their inhibitory receptors is crucial for natural killer(NK)cell education and activation; however,the influence of non-MHC-I ligands on NK cell education is seldom reported.Aim: To determine whether CD155-TIGIT interaction contributes to NK cell education in an MHC-I-independent manner.Methods: In vitro functional differences among WT NK cells,TIGIT-deficient NK cells and CD155-deficient NK cells were investigated by CD107a degranulation assay and cytokine analysis under different stimulation conditions.NK cell cytotoxicity was measured by in vitro 7AAD/CFSE assay and in vivo clearance assay.The intrinsic versus extrinsic effect of TIGIT was determined by mixed bone marrow chimera mice and the conjugate formation between NK cells and RMA-S-GFP tumor cells was observed by FACS-dependent conjugation experiments.Results: We showed that CD155,a ligand of the inhibitory receptor T cell Ig and ITIM domain(TIGIT),functioned as an MHC-I-independent missing-self molecule,and that CD155 deficiency rendered TIGIT+ NK cells hypo-responsive without affecting the activation of TIGIT-NK cells.Furthermore,using mouse models of TIGIT deficiency and NK cell-specific TIGIT deficiency,we demonstrated TIGIT-mediated recognition of host CD155 was critical for NK cell education and thus endowed NK cells with the ability to eliminate CD155-deficient targets such as allogenic splenocytes and tumor cells.Conclusions: Engagement of host CD155 via TIGIT receptor is involved in the acquisition of optimal NK cell effector function,representing a novel MHC-I-independent education program for NK cell tolerance and activation.