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The Role of the HLA Class I α2 Helix in Determining Ligand Hierarchy for the Killer Cell Ig-like Receptor 3DL1

Philippa M. Saunders, Bruce J. MacLachlan, Jacqueline Widjaja, Shu Cheng Wong, Clare V. L. Oates, Jamie Rossjohn, Julian P. Vivian and Andrew G. Brooks
J Immunol January 13, 2021, ji2001109; DOI: https://doi.org/10.4049/jimmunol.2001109
Philippa M. Saunders
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;
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Bruce J. MacLachlan
†Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia;
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Jacqueline Widjaja
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;
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Shu Cheng Wong
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;
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Clare V. L. Oates
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;
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Jamie Rossjohn
†Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia;
‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and
§Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom
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Julian P. Vivian
†Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia;
‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and
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Andrew G. Brooks
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia;
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Key Points

  • NK cells are differentially inhibited by HLA-ABw4 interactions with KIR3DL1.

  • Residues within the HLA class I α2 helix contribute to defining KIR3DL1 ligands.

  • KIR3DL1 binds HLA-ABw4 ligands via the same contacts as HLA-BBw4 ligands.

Abstract

HLA class I molecules that represent ligands for the inhibitory killer cell Ig-like receptor (KIR) 3DL1 found on NK cells are categorically defined as those HLA-A and HLA-B allotypes containing the Bw4 motif, yet KIR3DL1 demonstrates hierarchical recognition of these HLA-Bw4 ligands. To better understand the molecular basis underpinning differential KIR3DL1 recognition, the HLA-ABw4 family of allotypes were investigated. Transfected human 721.221 cells expressing HLA-A*32:01 strongly inhibited primary human KIR3DL1+ NK cells, whereas HLA-A*24:02 and HLA-A*23:01 displayed intermediate potency and HLA-A*25:01 failed to inhibit activation of KIR3DL1+ NK cells. Structural studies demonstrated that recognition of HLA-A*24:02 by KIR3DL1 used identical contacts as the potent HLA-B*57:01 ligand. Namely, the D1–D2 domains of KIR3DL1 were placed over the α1 helix and α2 helix of the HLA-A*24:02 binding cleft, respectively, whereas the D0 domain contacted the side of the HLA-A*24:02 molecule. Nevertheless, functional analyses showed KIR3DL1 recognition of HLA-A*24:02 was more sensitive to substitutions within the α2 helix of HLA-A*24:02, including residues Ile142 and Lys144. Furthermore, the presence of Thr149 in the α2 helix of HLA-A*25:01 abrogated KIR3DL1+ NK inhibition. Together, these data demonstrate a role for the HLA class I α2 helix in determining the hierarchy of KIR3DL1 ligands. Thus, recognition of HLA class I is dependent on a complex interplay between the peptide repertoire, polymorphisms within and proximal to the Bw4 motif, and the α2 helix. Collectively, the data furthers our understanding of KIR3DL1 ligands and will inform genetic association and immunogenetics studies examining the role of KIR3DL1 in disease settings.

Footnotes

  • ↵1 J.P.V. and A.G.B. are joint senior authors.

  • This work was supported by a program grant from the National Health and Medical Research Council of Australia (1113293) and the Australian Research Council (ARC) (CE140100011); J.R. is supported by an Australian ARC Laureate Fellowship.

  • The coordinates, structure factors, and validation reports presented in this article have been submitted to the Protein Data Bank (https://www.rcsb.org/) under accession numbers 7K80 and 7K81.

  • The online version of this article contains supplemental material.

  • Received September 30, 2020.
  • Accepted November 25, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 209 (3)
The Journal of Immunology
Vol. 209, Issue 3
1 Aug 2022
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The Role of the HLA Class I α2 Helix in Determining Ligand Hierarchy for the Killer Cell Ig-like Receptor 3DL1
Philippa M. Saunders, Bruce J. MacLachlan, Jacqueline Widjaja, Shu Cheng Wong, Clare V. L. Oates, Jamie Rossjohn, Julian P. Vivian, Andrew G. Brooks
The Journal of Immunology January 13, 2021, ji2001109; DOI: 10.4049/jimmunol.2001109

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The Role of the HLA Class I α2 Helix in Determining Ligand Hierarchy for the Killer Cell Ig-like Receptor 3DL1
Philippa M. Saunders, Bruce J. MacLachlan, Jacqueline Widjaja, Shu Cheng Wong, Clare V. L. Oates, Jamie Rossjohn, Julian P. Vivian, Andrew G. Brooks
The Journal of Immunology January 13, 2021, ji2001109; DOI: 10.4049/jimmunol.2001109
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