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Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J Clin Invest 2014 Aug;124(8):3455-68

Date

07/09/2014

Pubmed ID

25003188

Pubmed Central ID

PMC4109559

DOI

10.1172/JCI66108

Scopus ID

2-s2.0-84905482250   39 Citations

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.

Author List

Parish IA, Marshall HD, Staron MM, Lang PA, Brüstle A, Chen JH, Cui W, Tsui YC, Perry C, Laidlaw BJ, Ohashi PS, Weaver CT, Kaech SM

Author

Weiguo Cui PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Chronic Disease
Cytokines
Inflammation Mediators
Interleukin-10
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
MAP Kinase Signaling System
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Positive Regulatory Domain I-Binding Factor 1
Receptors, Antigen, T-Cell
T-Lymphocyte Subsets
Th1 Cells
Transcription Factors
jenkins-FCD Prod-406 0f9a74600e4e79798f8fa6f545ea115f3dd948b2