The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand

Michael Orihuela, David H. Margulies, Wayne M. Yokoyama

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73 Scopus citations

Abstract

Natural killer (NK) cells are inhibited from killing cellular targets by major histocompatibility complex (MHC) class I molecules. In the mouse, this can be mediated by the Ly-49A NK cell receptor that specifically binds the H- 2D(d) MHC class I molecule, then inhibits NK cell activity. Previous experiments have indicated that Ly-49A recognizes the α1/α2 domains of MHC class I and that no specific MHC-bound peptide appeared to be involved. We demonstrate here that alanine-substituted peptides, having only the minimal anchor motifs, stabilized H-2D(d) expression and provided resistance to H- 2D(d)-transfected, transporter associated with processing (TAP)-deficient cells from lysis by Ly-49A+ NK cells. Peptide-induced resistance was blocked only by an mAb that binds a conformational determinant on H-2D(d). Moreover, stabilization of 'empty' H-2D(d) heavy chains by exogenous β2-microglobulin did not confer resistance. In contrast to data for MHC class I-restricted T cells that are specific for peptides displayed by MHC molecules, these data indicate that NK cells are specific for a peptide-induced conformational determinant, independent of specific peptide. This fundamental distinction between NK cells and T cells further implies that NK cells are sensitive only to global changes in MHC class I conformation or expression, rather than to specific pathogen-encoded peptides. This is consistent with the 'missing self' hypothesis, which postulates that NK cells survey tissues for normal expression of MHC class I.

Original languageEnglish
Pages (from-to)11792-11797
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number21
DOIs
StatePublished - Oct 15 1996

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