Influence of xenogeneic beta2-microglobulin on functional recognition of H-2Kb by the NK cell inhibitory receptor Ly49C.
NK cells maintain self-tolerance through expression of inhibitory receptors that bind MHC class I (MHC-I) molecules. MHC-I can exist on the cell surface in several different forms, including "peptide-receptive" or PR-MHC-I that can bind exogenous peptide. PR-MHC-I molecules are short lived and, for H-2K(b), comprise approximately 10% of total MHC-I. In the present study, we confirm that signaling through the mouse NK inhibitory receptor Ly49C requires the presence of PR-K(b) and that this signaling is prevented when PR-K(b) is ablated by pulsing with a peptide that can bind to it with high affinity. Although crystallographic data indicate that Ly49C can engage H-2K(b) loaded with high-affinity peptide, our data suggest that this interaction does not generate an inhibitory signal. We also show that no signaling occurs when the PR-K(b) complex has mouse beta(2)-microglobulin (beta(2)m) replaced with human beta(2)m, although replacement with bovine beta(2)m has no effect. Furthermore, we show that beta(2)m exchange occurs preferentially in the PR-K(b) component of total H-2K(b). These conclusions were reached in studies modulating the sensitivity to lysis of both NK-resistant syngeneic lymphoblasts and NK-sensitive RMA-S tumor cells. We also show, using an in vivo model of lymphocyte recirculation, that engrafted lymphocytes are unable to survive NK attack when otherwise syngeneic lymphocytes express human beta(2)m. These findings suggest a qualitative extension of the "missing self" hypothesis to include NK inhibitory receptors that are restricted to the recognition of unstable forms of MHC-I, thus enabling NK cells to respond more quickly to events that decrease MHC-I synthesis.
Benoit
Loralyn A
LA
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Shannon
John
J
Chamberlain
John W
JW
Miller
Richard G
RG
D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology*; D000950:Antigens, Ly / Q000276:immunology*; D002417:Cattle; D003602:Cytotoxicity, Immunologic; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055630:Receptors, NK Cell Lectin-Like; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity; D001613:beta 2-Microglobulin / Q000276:immunology*
D015478:Antigens, Heterophile; D000950:Antigens, Ly; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; C527091:Klra3 protein, mouse; D037181:Lectins, C-Type; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055630:Receptors, NK Cell Lectin-Like; D001613:beta 2-Microglobulin