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

Brooke D. Huisman, Ning Guan, Timo Rückert, Lee Garner, Nishant K. Singh, Andrew J. McMichael, Geraldine M. Gillespie, Chiara Romagnani and Michael E. Birnbaum ()
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Brooke D. Huisman: Koch Institute for Integrative Cancer Research
Ning Guan: Koch Institute for Integrative Cancer Research
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
Andrew J. McMichael: University of Oxford
Geraldine M. Gillespie: University of Oxford
Chiara Romagnani: Innate Immunity, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Leibniz Institut
Michael E. Birnbaum: Koch Institute for Integrative Cancer Research

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40220-1

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