title: Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide.
abstract: Type I interferon (IFN) is crucial in host antiviral defense. Previous studies have described the pleiotropic role of type I IFNs on innate and adaptive immune cells during viral infection. Here, we demonstrate that natural killer (NK) cells from mice lacking the type I IFN-α receptor (Ifnar(-/-)) or STAT1 (which signals downstream of IFNAR) are defective in expansion and memory cell formation after mouse cytomegalovirus (MCMV) infection. Despite comparable proliferation, Ifnar(-/-) NK cells showed diminished protection against MCMV infection and exhibited more apoptosis compared with wild-type NK cells. Furthermore, we show that Ifnar(-/-) NK cells express increased levels of NK group 2 member D (NKG2D) ligands during viral infection and are susceptible to NK cell-mediated fratricide in a perforin- and NKG2D-dependent manner. Adoptive transfer of Ifnar(-/-) NK cells into NK cell-deficient mice reverses the defect in survival and expansion. Our study reveals a novel type I IFN-dependent mechanism by which NK cells evade mechanisms of cell death after viral infection.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Sharline
authors.initials: S
authors.lastname: Madera
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firth
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Beilke
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065 sunj@mskcc.org.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007370:Interferon Type I / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D054353:Perforin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C510467:perforin 1, mouse; D054353:Perforin; D053633:Receptor, Interferon alpha-beta