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Cross-Species Dependence of Ly49 Recognition on the Supertype Defining B-Pocket of a Class I MHC Molecule¹

Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

Ly49 recognition of MHC class I (MHC I) can be allele specific. However, the site of interaction on MHC I consists of highly conserved solvent-exposed amino acids, leaving it unclear how allele specificity occurs. In examining the specificity of mouse and rat Ly49, we noticed that MHC I ligands for mouse Ly49G and W, and the rat Ly49i2, typically share the HLA-B7 supertype, defined by a B-pocket that prefers a proline at position 2 in bound peptides. Through mutagenesis, we show that the supertype-defining B-pocket of RT1-A1^c controls its allele-specific recognition by the syngeneic rat Ly49i2 inhibitory receptor and xenogeneic mouse inhibitory Ly49G and activating Ly49W receptors. Single amino acid substitutions in the B-pocket that did not prevent peptide binding disrupted Ly49 recognition. In contrast, single mutations in other regions of the peptide-binding groove had no effect. We provide a model whereby the B-pocket dictates the conformation of conserved residues at the Ly49 interaction site below, defining Ly49 allele specificity for MHC I. Therefore, at least some Ly49 may recognize supertypes, detectable even across species, and are sensitive to polymorphisms in the supertype-defining B-pocket. This would ensure that expression of specific MHC I supertypes capable of Ag presentation to T cells is sensed by NK cells, and if lacking, targets a cell for elimination, suggesting a supertype-mediated link between innate and adaptive immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an operating grant from the Canadian Institutes for Health Research (to K.P.K.). K.J.L. was supported by Canadian Institutes for Health Research and Alberta Heritage Foundation for Medical Research studentships. K.P.K. is an Alberta Heritage Foundation for Medical Research Scientist.

² Address correspondence and reprint requests to Dr. Kevin P. Kane, Department of Medical Microbiology and Immunology, 6-60 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. E-mail address: kevin.kane{at}ualberta.ca

³ Abbreviations used in this paper: KIR, killer cell Ig-like receptor; MHC I, MHC class I; EGFP, enhanced GFP.

This article has been cited by other articles:

				K. J. Lavender, H. H. Chau, and K. P. Kane Distinctive Interactions at Multiple Site 2 Subsites by Allele-Specific Rat and Mouse Ly49 Determine Functional Binding and Class I MHC Specificity J. Immunol., November 15, 2007; 179(10): 6856 - 6866. [Abstract] [Full Text] [PDF]