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Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C.

Authors
  • Sim, Malcolm J W1, 2
  • Rajagopalan, Sumati1
  • Altmann, Daniel M3
  • Boyton, Rosemary J3
  • Sun, Peter D2
  • Long, Eric O4
  • 1 Molecular and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
  • 2 Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
  • 3 Lung Immunology Group, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom. , (United Kingdom)
  • 4 Molecular and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Jun 25, 2019
Volume
116
Issue
26
Pages
12964–12973
Identifiers
DOI: 10.1073/pnas.1903781116
PMID: 31138701
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01-restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01. Copyright © 2019 the Author(s). Published by PNAS.

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