title: Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells.
abstract: Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficient for effective control of MCMV infection. Additionally, during the host response to infection, distinct immune and non-immune cells elaborate a variety of pleiotropic cytokines which have the potential to impact viral pathogenesis, NK cells, and other immune functions, both directly and indirectly. While the effects of various immune deficiencies have been examined for general antiviral phenotypes, their direct effects on Ly49H-dependent MCMV control are poorly understood. To specifically interrogate Ly49H-dependent functions, herein we employed an in vivo viral competition approach to show Ly49H-dependent MCMV control is specifically mediated through cytotoxicity but not IFNγ production. Whereas m157 induced Ly49H-dependent degranulation, efficient cytotoxicity also required either IL-12 or type I interferon (IFN-I) which acted directly on NK cells to produce granzyme B. These studies demonstrate that both of these distinct NK cell-intrinsic mechanisms are integrated for optimal viral control by NK cells.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Bijal A
authors.initials: BA
authors.lastname: Parikh
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Sytse J
authors.initials: SJ
authors.lastname: Piersma
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pak-Wittel
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016207:Cytokines; C527096:Klra8 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A