Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1
Ian A. Parish, … , Casey T. Weaver, Susan M. Kaech
Ian A. Parish, … , Casey T. Weaver, Susan M. Kaech
Published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3455-3468. https://doi.org/10.1172/JCI66108.
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Research Article Immunology

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

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

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Figure 4

T cell–derived IL-10 suppresses virus-specific T cell responses and viral clearance during chronic LCMV infection.

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T cell–derived IL-10 suppresses virus-specific T cell responses and vira...
Irradiated BM chimeras were generated with either 100% Il10–/– BM (Total KO), 75% Tcra–/– plus 25% B6 BM (T cell WT), 75% Tcra–/– plus 25% Il10–/– BM (T cell KO), 75% Cd4–/– plus 25% B6 BM (CD4 T cell WT), or 75% Cd4–/– plus 25% Il10–/– BM (CD4 T cell KO). BM chimeras were infected with 2 × 106 PFU LCMV-Cl.13, and the T cell response and viral load were measured on day 8 p.i. (A and B) Bar graphs show the percentage of either tetramer+ cells specific for the indicated epitopes (A) or IFN-γ–producing (B) CD8+ T cells in response to either GP33 (CD8+GP33+) or NP396 (CD8+NP396+) peptide stimulation (left 2 panels) or the percentage of IFN-γ–producing CD4+ T cells in response to GP66 peptide stimulation (CD4+GP66+, far right panel). (C) Viral titers in the liver or kidney. *P < 0.05; **P < 0.01; NS, indicates P > 0.05. Data were pooled from 2 independent experiments (n = 4–8 mice/group).