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Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis

2023; American Association for the Advancement of Science; Volume: 8; Issue: 90 Linguagem: Inglês

10.1126/sciimmunol.adi3974

2470-9468

Stéphanie Jost, Olivier Lucar, Esther Lee, Taylor Yoder, Kyle Kroll, Sho K. Sugawara, Scott Smith, Rhianna Jones, George Tweet, Alexandra Werner, Phillip J. Tomezsko, Haley L. Dugan, Joshua Ghofrani, Philippe Rascle, Marcus Altfeld, Michaela Müller‐Trutwin, Paul Goepfert, R. Keith Reeves,

HIV Research and Treatment

Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4β7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.