title: A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells.
abstract: Major histocompatibility class I (MHC-I)-specific inhibitory receptors on natural killer (NK) cells (iNKRs) tolerize mature NK cell responses toward normal cells. NK cells generate cytolytic responses to virus-infected or malignant target cells with altered or decreased MHC-I surface expression due to the loss of tolerizing ligands. The NKG2A/CD94 iNKR suppresses NK cell responses through recognition of the non-classical MHC-I, HLA-E. We used HIV-infected primary T-cells as targets in an in vitro cytolytic assay with autologous NK cells from healthy donors. In these experiments, primary NKG2A/CD94(+) NK cells surprisingly generated the most efficient responses toward HIV-infected T-cells, despite high HLA-E expression on the infected targets. Since certain MHC-I-presented peptides can alter recognition by iNKRs, we hypothesized that HIV-1-derived peptides presented by HLA-E on infected cells may block engagement with NKG2A/CD94, thereby engendering susceptibility to NKG2A/CD94(+) NK cells. We demonstrate that HLA-E is capable of presenting a highly conserved peptide from HIV-1 capsid (AISPRTLNA) that is not recognized by NKG2A/CD94. We further confirmed that HLA-C expressed on HIV-infected cells restricts attack by KIR2DL(+) CD56(dim) NK cells, in contrast to the efficient responses by CD56(bright) NK cells, which express predominantly NKG2A/CD94 and lack KIR2DLs. These findings are important since the use of NK cells was recently proposed to treat latently HIV-1-infected patients in combination with latency reversing agents. Our results provide a mechanistic basis to guide these future clinical studies, suggesting that ex vivo-expanded NKG2A/CD94(+) KIR2DL(-) NK cells may be uniquely beneficial.
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Davis
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cogswell
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Hamish
authors.initials: H
authors.lastname: Scott
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mertsching
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Boucau
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wambua
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.affiliation: Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Barker
mesh_terms: D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology; D010455:Peptides / Q000276:immunology; D055607:Receptors, Natural Killer Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D000097625:HLA-E Antigens
chemical_list: D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens
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