Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction
Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction
ABSTRACT For over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities – HIV and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, 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 firmly dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous and novel assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through RNA-Seq transcriptomic fingerprints and complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, α4β7 and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind formation of antigen-specific memory NK cells, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.
Sugawara Sho、Jones Rhianna、Altfeld Marcus、Grundhoff Adam、Muller-Trutwin Michaela、Reeves R. Keith、Yoder Taylor、Kroll Kyle、Goepfert Paul、Smith Scott、Dugan Haley L.、Tweet George、Werner Alexandra、Tomezsko Phillip J.、Jost Stephanie、Lucar Olivier、Ghofrani Joshua
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolHeinrich Pette Institute, Leibniz Institute for Experimental VirologyHeinrich Pette Institute, Leibniz Institute for Experimental VirologyInstitut Pasteur, HIV, Inflammation and Persistence UnitCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School||Ragon Institute of Massachusetts General Hospital, MIT, and HarvardCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolUniversity of Alabama at BirminghamCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolRagon Institute of Massachusetts General Hospital, MIT, and HarvardCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolRagon Institute of Massachusetts General Hospital, MIT, and HarvardCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School
基础医学生物科学研究方法、生物科学研究技术
Sugawara Sho,Jones Rhianna,Altfeld Marcus,Grundhoff Adam,Muller-Trutwin Michaela,Reeves R. Keith,Yoder Taylor,Kroll Kyle,Goepfert Paul,Smith Scott,Dugan Haley L.,Tweet George,Werner Alexandra,Tomezsko Phillip J.,Jost Stephanie,Lucar Olivier,Ghofrani Joshua.Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction[EB/OL].(2025-03-28)[2025-05-08].https://www.biorxiv.org/content/10.1101/2020.11.09.374348.点此复制
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