Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

J Clin Invest. 2014 Aug;124(8):3455-68. doi: 10.1172/JCI66108. Epub 2014 Jul 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Cytokines / biosynthesis
  • Inflammation Mediators / metabolism
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / metabolism
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / pathogenicity
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Transcription Factors / metabolism*

Substances

  • Cytokines
  • IL10 protein, mouse
  • Inflammation Mediators
  • Prdm1 protein, mouse
  • Receptors, Antigen, T-Cell
  • Transcription Factors
  • Interleukin-10
  • Positive Regulatory Domain I-Binding Factor 1