title: Influenza Virus Targets Class I MHC-Educated NK Cells for Immunoevasion.
abstract: The immune response to influenza virus infection comprises both innate and adaptive defenses. NK cells play an early role in the destruction of tumors and virally-infected cells. NK cells express a variety of inhibitory receptors, including those of the Ly49 family, which are functional homologs of human killer-cell immunoglobulin-like receptors (KIR). Like human KIR, Ly49 receptors inhibit NK cell-mediated lysis by binding to major histocompatibility complex class I (MHC-I) molecules that are expressed on normal cells. During NK cell maturation, the interaction of NK cell inhibitory Ly49 receptors with their MHC-I ligands results in two types of NK cells: licensed ("functional"), or unlicensed ("hypofunctional"). Despite being completely dysfunctional with regard to rejecting MHC-I-deficient cells, unlicensed NK cells represent up to half of the mature NK cell pool in rodents and humans, suggesting an alternative role for these cells in host defense. Here, we demonstrate that after influenza infection, MHC-I expression on lung epithelial cells is upregulated, and mice bearing unlicensed NK cells (Ly49-deficient NKCKD and MHC-I-deficient B2m-/- mice) survive the infection better than WT mice. Importantly, transgenic expression of an inhibitory self-MHC-I-specific Ly49 receptor in NKCKD mice restores WT influenza susceptibility, confirming a direct role for Ly49. Conversely, F(ab')2-mediated blockade of self-MHC-I-specific Ly49 inhibitory receptors protects WT mice from influenza virus infection. Mechanistically, perforin-deficient NKCKD mice succumb to influenza infection rapidly, indicating that direct cytotoxicity is necessary for unlicensed NK cell-mediated protection. Our findings demonstrate that Ly49:MHC-I interactions play a critical role in influenza virus pathogenesis. We suggest a similar role may be conserved in human KIR, and their blockade may be protective in humans.
authors.affiliation: College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Kingdom of Saudi Arabia.|Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ahmad Bakur
authors.initials: AB
authors.lastname: Mahmoud
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Tu
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wight
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.|Cairo University Research Park, Faculty of Agriculture, Cairo University, Giza, Egypt.
authors.forename: Haggag S
authors.initials: HS
authors.lastname: Zein
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mir Munir A
authors.initials: MM
authors.lastname: Rahim
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Harman S
authors.initials: HS
authors.lastname: Sekhon
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Earl G
authors.initials: EG
authors.lastname: Brown
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Makrigiannis
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003433:Crosses, Genetic; D057131:Immune Evasion; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D055650:NK Cell Lectin-Like Receptor Subfamily A; D052899:Pore Forming Cytotoxic Proteins; D054340:Receptors, KIR; D001613:beta 2-Microglobulin; C483886:perforin, mouse