title: Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence.
abstract: CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Mathew
authors.identifier: http://orcid.org/0000-0002-9280-5281
authors.initials: M
authors.lastname: Clement
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Morgan
authors.initials: M
authors.lastname: Marsden
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Stacey
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Juneid
authors.initials: J
authors.lastname: Abdul-Karim
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gimeno Brias
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Costa Bento
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Martin J
authors.identifier: http://orcid.org/0000-0002-4120-0688
authors.initials: MJ
authors.lastname: Scurr
authors.affiliation: Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Research Department, MedImmune LLC, Gaithersburg, MD, United States of America.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Carlesso
authors.affiliation: Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Simon A
authors.identifier: http://orcid.org/0000-0001-7297-9711
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Godkin
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.affiliation: Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.|Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Humphreys
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D064094:Interleukin-27 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D007370:Interferon Type I; D064094:Interleukin-27; D016753:Interleukin-10