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 5

IL-10 production is restricted to exhausted CD8+ T cells and Th1 cells with diminished inflammatory function.

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IL-10 production is restricted to exhausted CD8+ T cells and Th1 cells w...
(A) Splenic Thy1.1+ CD8+GP33+ tetramer+ cell phenotypes in LCMV-Cl.13–infected (2 × 106 PFU) 10BiT mice on day 8 p.i. Data are representative of 2 independent experiments (n = 5 mice). (B) Correlation between cytokine or CD107a expression and Thy1.1 levels within α-CD3–stimulated CD8+ T cells on day 8 p.i. with Cl.13. The TNF-α plot was gated on CD8+IFN-γ+ cells. Data are representative of 2 independent experiments (n = 5 mice). Numbers represent the quadrant frequency. (C) The Tfh and Th1 phenotype of splenic Thy1.1+ CD4+GP66+ tetramer+ 10BiT cells on day 8 p.i. with Cl.13. Data are representative of 3 independent experiments (n = 8–10 mice). (D) The Thy1.1+ 10BiT cell proportion within the non-Tfh (PSGL1hiCXCR5lo) and Tfh (PSGL1loCXCR5hi) cell populations on days 8 and 20 p.i. with Cl.13. Data were pooled from 2 to 4 independent experiments (n = 11–13/time point). ***P < 0.001. (E) Plots showing IFN-γ and CD107a production within α-CD3–stimulated CD4+ T cells or TNF-α and IL-2 production within CD4+IFN-γ+ cells on day 8 p.i. with Cl.13. Data are representative of 2 to 3 independent experiments (n = 5–8 mice total). Numbers represent the quadrant frequency. (F) Congenically marked Ly5.1+ STg 10BiT cells were transferred into B6 mice subsequently infected with 2 × 106 PFU LCMV-Cl.13. Donor Thy1.1+ and Thy1.1– STg 10BiT cells were sorted on day 8 p.i., and Il10 and Il21 mRNA levels were assessed by quantitative RT-PCR. *P < 0.05; NS, indicates P > 0.05. Data were pooled from 3 independent experiments.