title: TRAIL+ NK cells control CD4+ T cell responses during chronic viral infection to limit autoimmunity.
abstract: Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4(+) T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4(+) T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren's-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Iona S
authors.initials: IS
authors.lastname: Schuster
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Brizard
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Coudert
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Marie J
authors.initials: MJ
authors.lastname: Estcourt
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Mitali
authors.initials: M
authors.lastname: Manzur
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia. Electronic address: mariapia@lei.org.au.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology / Q000821:virology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse