title: IL-10 suppression of NK/DC crosstalk leads to poor priming of MCMV-specific CD4 T cells and prolonged MCMV persistence.
abstract: IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10(-/-) mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.
authors.affiliation: Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
authors.forename: Sanja
authors.initials: S
authors.lastname: Mandaric
authors.forename: Senta M
authors.initials: SM
authors.lastname: Walton
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Kirsten
authors.initials: K
authors.lastname: Richter
authors.forename: Mathilde J H
authors.initials: MJ
authors.lastname: Girard-Madoux
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Antonija
authors.initials: A
authors.lastname: Zurunic
authors.forename: Masahito
authors.initials: M
authors.lastname: Kamanaka
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D016753:Interleukin-10