title: Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1.
abstract: During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.forename: Heather D
authors.initials: HD
authors.lastname: Marshall
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Staron
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Chen
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.forename: Yao-Chen
authors.initials: YC
authors.lastname: Tsui
authors.forename: Curtis
authors.initials: C
authors.lastname: Perry
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Laidlaw
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; C513258:Prdm1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D016753:Interleukin-10; D000074462:Positive Regulatory Domain I-Binding Factor 1