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High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation

Author

Listed:
  • Brooke D. Huisman

    (Koch Institute for Integrative Cancer Research
    Department of Biological Engineering, MIT)

  • Ning Guan

    (Koch Institute for Integrative Cancer Research
    Department of Biological Engineering, MIT)

  • Timo Rückert

    (Innate Immunity, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Leibniz Institut)

  • Lee Garner

    (University of Oxford)

  • Nishant K. Singh

    (Koch Institute for Integrative Cancer Research
    Ragon Institute of MGH, MIT, and Harvard)

  • Andrew J. McMichael

    (University of Oxford)

  • Geraldine M. Gillespie

    (University of Oxford)

  • Chiara Romagnani

    (Innate Immunity, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Leibniz Institut
    Charité - Universitätsmedizin Berlin)

  • Michael E. Birnbaum

    (Koch Institute for Integrative Cancer Research
    Department of Biological Engineering, MIT
    Ragon Institute of MGH, MIT, and Harvard)

Abstract

HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown HLA-E can present diverse peptides to NK cells and T cells, the HLA-E repertoire recognized by CD94/NKG2x has remained poorly defined, with only a limited number of peptide ligands identified. Here we screen a yeast-displayed peptide library in the context of HLA-E to identify 500 high-confidence unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C. Utilizing the sequences identified via yeast display selections, we train prediction algorithms and identify human and cytomegalovirus (CMV) proteome-derived, HLA-E-presented peptides capable of binding and signaling through both CD94/NKG2A and CD94/NKG2C. In addition, we identify peptides which selectively activate NKG2C+ NK cells. Taken together, characterization of the HLA-E-binding peptide repertoire and identification of NK activity-modulating peptides present opportunities for studies of NK cell regulation in health and disease, in addition to vaccine and therapeutic design.

Suggested Citation

  • Brooke D. Huisman & Ning Guan & Timo Rückert & Lee Garner & Nishant K. Singh & Andrew J. McMichael & Geraldine M. Gillespie & Chiara Romagnani & Michael E. Birnbaum, 2023. "High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40220-1
    DOI: 10.1038/s41467-023-40220-1
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    References listed on IDEAS

    as
    1. Lucy C. Walters & Karl Harlos & Simon Brackenridge & Daniel Rozbesky & Jordan R. Barrett & Vitul Jain & Thomas S. Walter & Chris A. O’Callaghan & Persephone Borrow & Mireille Toebes & Scott G. Hansen , 2018. "Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. C. Garrett Rappazzo & Brooke D. Huisman & Michael E. Birnbaum, 2020. "Repertoire-scale determination of class II MHC peptide binding via yeast display improves antigen prediction," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Veronique M. Braud & David S. J. Allan & Christopher A. O'Callaghan & Kalle Söderström & Annalisa D'Andrea & Graham S. Ogg & Sasha Lazetic & Neil T. Young & John I. Bell & Joseph H. Phillips & Lewis L, 1998. "HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C," Nature, Nature, vol. 391(6669), pages 795-799, February.
    4. Yu-Xiong Feng & Dexter X. Jin & Ethan S. Sokol & Ferenc Reinhardt & Daniel H. Miller & Piyush B. Gupta, 2017. "Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
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