title: Cytomegalovirus immunoevasin reveals the physiological role of "missing self" recognition in natural killer cell dependent virus control in vivo.
abstract: Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8(+) T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell-mediated killing via the "missing self" axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the "self" signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell- and MHC I-dependent manner. NK cell-mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self-dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.
authors.affiliation: Department of Histology and Embryology, Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia.
authors.forename: Marina
authors.initials: M
authors.lastname: Babić
authors.forename: Michal
authors.initials: M
authors.lastname: Pyzik
authors.forename: Biljana
authors.initials: B
authors.lastname: Zafirova
authors.forename: Maja
authors.initials: M
authors.lastname: Mitrović
authors.forename: Višnja
authors.initials: V
authors.lastname: Butorac
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Astrid
authors.initials: A
authors.lastname: Krmpotić
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjić
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006023:Glycoproteins / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018146:Muromegalovirus / Q000276:immunology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000502:physiology; D014764:Viral Proteins / Q000276:immunology* / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D006183:H-2 Antigens; C527088:Klra1 protein, mouse; C527086:Klrk1 protein, mouse; D008562:Membrane Glycoproteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014764:Viral Proteins; C104832:gp34 protein, cytomegalovirus; C104783:m152 protein, cytomegalovirus