Cross-species dependence of Ly49 recognition on the supertype defining B-pocket of a class I MHC molecule.
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.
Lavender
Kerry J
KJ
Department of Medical Microbiology and Immunology, 6-60 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Kane
Kevin P
KP
D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D000950:Antigens, Ly / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000737:chemistry / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D055650:NK Cell Lectin-Like Receptor Subfamily A; D051381:Rats; D011919:Rats, Inbred Strains; D055630:Receptors, NK Cell Lectin-Like
D000950:Antigens, Ly; D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I; C527095:Klra7 protein, mouse; D037181:Lectins, C-Type; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055630:Receptors, NK Cell Lectin-Like