title: Specific dysregulation of IFNγ production by natural killer cells confers susceptibility to viral infection.
abstract: Natural Killer (NK) cells contribute to the control of viral infection by directly killing target cells and mediating cytokine release. In C57BL/6 mice, the Ly49H activating NK cell receptor plays a key role in early resistance to mouse cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. Here we show that transgenic expression of Ly49H failed to provide protection against MCMV infection in the naturally susceptible A/J mouse strain. Characterization of Ly49H(+) NK cells from Ly49h-A transgenic animals showed that they were able to mount a robust cytotoxic response and proliferate to high numbers during the course of infection. However, compared to NK cells from C57BL/6 mice, we observed an intrinsic defect in their ability to produce IFNγ when challenged by either m157-expressing target cells, exogenous cytokines or chemical stimulants. This effect was limited to NK cells as T cells from C57BL/6 and Ly49h-A mice produced comparable cytokine levels. Using a panel of recombinant congenic strains derived from A/J and C57BL/6 progenitors, we mapped the genetic basis of defective IFNγ production to a single 6.6 Mb genetic interval overlapping the Ifng gene on chromosome 10. Inspection of the genetic interval failed to reveal molecular differences between A/J and several mouse strains showing normal IFNγ production. The chromosome 10 locus is independent of MAPK signalling or decreased mRNA stability and linked to MCMV susceptibility. This study highlights the existence of a previously uncovered NK cell-specific cis-regulatory mechanism of Ifnγ transcript expression potentially relevant to NK cell function in health and disease.
authors.affiliation: Department of Human Genetics and Department of Microbiology and Immunology, McGill University, Life Sciences Complex, Montreal, Quebec, Canada.
authors.forename: Nassima
authors.initials: N
authors.lastname: Fodil
authors.affiliation: Biochemistry Department, McGill University, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Department of Human Genetics and Department of Microbiology and Immunology, McGill University, Life Sciences Complex, Montreal, Quebec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Moussa
authors.affiliation: Department of Human Genetics and Department of Microbiology and Immunology, McGill University, Life Sciences Complex, Montreal, Quebec, Canada.
authors.forename: Gregory Allan
authors.initials: GA
authors.lastname: Boivin
authors.affiliation: Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Tania
authors.initials: T
authors.lastname: Di Pietrantonio
authors.affiliation: Biochemistry Department, McGill University, Montréal, Québec, Canada.
authors.forename: Irena
authors.initials: I
authors.lastname: Radovanovic
authors.affiliation: Department of Human Genetics and Department of Microbiology and Immunology, McGill University, Life Sciences Complex, Montreal, Quebec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Dumaine
authors.affiliation: McGill Centre for Bioinformatics and School of Computer Science, McGill University, Montréal, Québec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanchette
authors.affiliation: Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
authors.affiliation: Biochemistry Department, McGill University, Montréal, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.affiliation: Department of Human Genetics and Department of Microbiology and Immunology, McGill University, Life Sciences Complex, Montreal, Quebec, Canada.
authors.forename: Silvia Marina
authors.initials: SM
authors.lastname: Vidal
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000276:immunology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A; D020871:RNA Stability / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C527096:Klra8 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D014764:Viral Proteins; D007371:Interferon-gamma