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

Ian A. Parish, Heather D. Marshall, Matthew M. Staron, Philipp A. Lang, Anne Brüstle, Jonathan H. Chen, Weiguo Cui, Yao Chen Tsui, Curtis Perry, Brian J. Laidlaw, Pamela S. Ohashi, Casey T. Weaver, Susan M. Kaech

Research output: Contribution to journalArticlepeer-review

63 Scopus 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.

Original languageEnglish
Pages (from-to)3455-3468
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

Fingerprint

Dive into the research topics of 'Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1'. Together they form a unique fingerprint.

Cite this