KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand with a Bw6 Motif

PLoS Pathogens

David T. Evans¹  William J. Neidermyer Jr²  Arnaud D. Colantonio²  Benjamin N. Bimber³  R. Paul Johnson⁴  R. Keith Reeves⁴  Galit Alter⁵  Mary Carrington⁵  Marcus Altfeld⁵  David H. O'Connor⁵ 

[1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI Frederick, Frederick, Maryland, United States of America;Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America;Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America;Division of Immunology, New England Primate Research Center, Southborough, Massachusetts, United States of America;Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, United States of America

关键词: NK cells;    Cell staining;    Macaque;    Major histocompatibility complex;    Cytotoxic T cells;    Rhesus monkeys;    T cells;    MHC class I genes;   

DOI  :  10.1371/journal.ppat.1001316

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05+ macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.

【 授权许可】

CC BY