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
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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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 1

IL-10 reporter expression kinetics during chronic versus acute LCMV infection.

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IL-10 reporter expression kinetics during chronic versus acute LCMV infe...
(A and B) 10BiT reporter mice were infected with either 2 × 105 PFU LCMV-Arm or 1 × 102 PFU LCMV-Cl.13 (Acute Cl.13) to establish an acute infection or 2 × 106 PFU LCMV-Cl.13 (Chronic Cl.13) to establish a chronic infection. The Thy1.1 IL-10 reporter–positive cell percentage was measured over time in either spleen (A and B), blood (B), or BM (B). Gates used to determine the Thy1.1+ percentage were set using transgene-negative control animals. (A) Representative Thy1.1 staining in splenocytes and (B) data compiled from 2 to 5 independent experiments (n = 4–16 mice/time point). (C) 10BiT reporter mice were infected with 2 × 106 PFU LCMV-Cl.13, and on day 8 p.i., FACS-purified Thy1.1+ and Thy1.1– splenocytes were left unstimulated or were stimulated for 6 hours with PMA and ionomycin. Supernatant IL-10 concentrations were then measured by ELISA. Bar graphs show the pooled data of the IL-10 amount produced per 1 × 106 cells from 3 independent experiments.