Major histocompatibility complex class I as a ligand for natural killer cell recognition

grantor: University of TorontoNatural killer cell (NK)-mediated cytotoxicity involves two families of receptors: activating receptors that trigger lysis of the target cells being recognized and inhibitory receptors specific primarily for Major Histocompatibility Complex Class I (MHC-I) on the target cell surface that can override the activating signal. Cells expressing reduced surface MHC-I have been shown to be targets for NK-mediated cytotoxicity. MHC-I molecules on the cell surface can be classified into molecules made stable by the binding of high affinity peptide (p H-MHC-I) or unstable molecules potentially capable of being stabilized by binding high affinity peptide (peptide receptive, PR-MHC-I). It has been previously shown that the Ly49A inhibitory receptor recognizes pH-D d. Our data suggest the existence of other NK inhibitory receptor(s) recognizing PR-Kb, -Db, -Dd, or -Kd. During the search for such receptor(s), we found that the inhibitory receptor Ly49CB6 recognizes PR-Kb but does not recognize Kb once they have bound high affinity peptide. Furthermore, we have measured the stability of surface pH-K b and PR-Kb molecules in the presence of BFA. p H-Kb has a t1/2 of ~45 ± 3h and surface PR-Kb has a t1/2 of approximately 30 ± 4 min at 37°C. These observations suggest a possible explanation as to why some virus infected cells become targets for syngeneic NK cells even without a major reduction in total surface MHC-I expression. Our recent study on cells infected with adenovirus types 5 (Ad5) or 12 (Ad12) shows that Ad5 infected cells lose surface PR-Kb expression and become sensitive to NK-lysis within 9h post-infection while Ad12 infected cells have normal PR-Kb expression and remain resistant to NK-lysis until 42h post-infection. Furthermore, the total Kb expression remains unaltered on cells infected by either Ad5 or Ad12. These observations agree with our hypothesis and further suggest that recognition of PR-MHC I may be one of the mechanisms employed by NK cells to detect viral infection.Ph.D