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

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Title: Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C
Authors: Sim, M
Rajagopalan, S
Altmann, D
Boyton, R
Sun, PD
Long, E
Item Type: Journal Article
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.
Issue Date: 25-Jun-2019
Date of Acceptance: 2-May-2019
URI: http://hdl.handle.net/10044/1/70456
DOI: 10.1073/pnas.1903781116
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: 12964
End Page: 12973
Journal / Book Title: Proceedings of the National Academy of Sciences
Volume: 116
Issue: 26
Copyright Statement: © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: National Institutes of Health
Wellcome Trust
Funder's Grant Number: HHSN272200900046C
095472/Z/11/Z
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NK cells
bacteria
KIR
HLA-C
RecA
MHC CLASS-I
NATURAL-KILLER-CELLS
IMMUNOGLOBULIN-LIKE RECEPTOR
E3 UBIQUITIN LIGASE
INHIBITORY RECEPTOR
CRYSTAL-STRUCTURE
DENDRITIC CELLS
DIRECT BINDING
MATERNAL KIR
RECOGNITION
HLA-C
KIR
NK cells
RecA
bacteria
Amino Acid Motifs
Bacteria
Cell Line
Epitopes
HLA-C Antigens
Humans
Killer Cells, Natural
Rec A Recombinases
Receptors, KIR
Killer Cells, Natural
Cell Line
Humans
Bacteria
Rec A Recombinases
HLA-C Antigens
Epitopes
Amino Acid Motifs
Receptors, KIR
Publication Status: Published
Online Publication Date: 2019-05-28
Appears in Collections:Department of Immunology and Inflammation
Department of Infectious Diseases
Faculty of Medicine