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Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C

Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet M. Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. Long, Rosemary J. Boyton
doi: https://doi.org/10.1101/096958
Malcolm J. W. Sim
1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA
2Lung Immunology Group, Department of Medicine, Imperial College London, London, UK.
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Stacy A. Malaker
3Departments of Chemistry, University of Virginia, Charlottesville, VA, USA
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Ayesha Khan
2Lung Immunology Group, Department of Medicine, Imperial College London, London, UK.
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Janet M. Stowell
2Lung Immunology Group, Department of Medicine, Imperial College London, London, UK.
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Jeffrey Shabanowitz
3Departments of Chemistry, University of Virginia, Charlottesville, VA, USA
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Mary E. Peterson
1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA
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Sumati Rajagopalan
1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA
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Donald F. Hunt
3Departments of Chemistry, University of Virginia, Charlottesville, VA, USA
4Departments of Pathology, University of Virginia, Charlottesville, VA, USA
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Daniel M. Altmann
2Lung Immunology Group, Department of Medicine, Imperial College London, London, UK.
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Eric O. Long
1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA
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  • For correspondence: eLong@nih.gov r.boyton@imperial.ac.uk
Rosemary J. Boyton
2Lung Immunology Group, Department of Medicine, Imperial College London, London, UK.
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  • For correspondence: eLong@nih.gov r.boyton@imperial.ac.uk
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Abstract

Background Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80) and KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model does not capture allelic diversity in HLA-C or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.

Results The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides, or predicted HIV Gag peptides, by HLA-C can promote KIR cross-reactive binding.

Conclusions KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, which provides an explanation for why KIR2DL3–C1 interactions appear weaker than KIR2DL1–C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR–HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.

  • Abbreviations

    CD3
    cluster of differentiation 3
    CHAPS
    3-[(3-Cholamidopropyl) dimethyl ammonio]-1-propanesulfonate
    CMV
    Cytomegalovirus
    EBV
    Epstein–Barr virus
    EDTA
    Ethylenediaminetetraacetic acid
    FACS
    Fluorescence activated cell sorting
    GFP
    Green fluorescent protein
    HCV
    Herpes simplex virus
    HIV
    Human immunodeficiency virus
    HLA
    Human leukocyte antigen
    KIR
    Killer-cell immunoglobulin-like receptor
    MFI
    Median fluorescence intensity
    NK
    cell Natural killer cell
    PBMC
    Peripheral blood mononuclear cell
    PBS
    Phosphate-buffered saline
    SEM
    Standard error of the mean
    SP
    single positive
    TAP
    Transporter associated with antigen processing
    VSV
    Vesicular stomatitis virus
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted December 27, 2016.
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    Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C
    Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet M. Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. Long, Rosemary J. Boyton
    bioRxiv 096958; doi: https://doi.org/10.1101/096958
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    Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C
    Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet M. Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. Long, Rosemary J. Boyton
    bioRxiv 096958; doi: https://doi.org/10.1101/096958

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