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Influence of Xenogeneic ₂-Microglobulin on Functional Recognition of H-2K^b by the NK Cell Inhibitory Receptor Ly49C¹

Loralyn A. Benoit^*,, John Shannon, John W. Chamberlain^*, and Richard G. Miller^2,*,

^* Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada; and Program in Infection, Immunity, Injury and Repair, Hospital for Sick Children, Toronto, Ontario, Canada

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 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 ₂-microglobulin (₂m) replaced with human ₂m, although replacement with bovine ₂m has no effect. Furthermore, we show that ₂m 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 ₂m. 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.

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				L. A. Benoit and R. Tan Xenogeneic beta2-Microglobulin Substitution Alters NK Cell Function J. Immunol., August 1, 2007; 179(3): 1466 - 1474. [Abstract] [Full Text] [PDF]