High-Dimensional Characterization of IL-10 Production and IL-10-Dependent Regulation during Primary Gammaherpesvirus Infection

Immunohorizons. 2019 Mar 21;3(3):94-109. doi: 10.4049/immunohorizons.1800088.

Abstract

IL-10 is a potent immunomodulatory cytokine produced by multiple cell types to restrain immune activation. Many herpesviruses use the IL-10 pathway to facilitate infection, but how endogenous IL-10 is regulated during primary infection in vivo remains poorly characterized. In this study, we infected mice with murine gammaherpesvirus 68 (γHV68) and analyzed the production and genetic contribution of IL-10 by mass cytometry (cytometry by time-of-flight) analysis. γHV68 infection elicited a breadth of effector CD4 T cells in the lungs of acutely infected mice, including a highly activated effector subset that coexpressed IFN-γ, TNF-α, and IL-10. By using IL-10 GFP transcriptional reporter mice, we identified that IL-10 was primarily expressed within CD4 T cells during acute infection in the lungs. IL10gfp-expressing CD4 T cells were highly proliferative and characterized by the expression of multiple coinhibitory receptors, including PD-1 and LAG-3. When we analyzed acute γHV68 infection of IL-10-deficient mice, we found that IL-10 limits the frequency of both myeloid and effector CD4 T cell subsets in the infected lung, with minimal changes at a distant mucosal site. These data emphasize the unique insights that high-dimensional analysis can afford in investigating antiviral immunity and provide new insights into the breadth, phenotype, and function of IL-10-expressing effector CD4 T cells during acute virus infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gammaherpesvirinae / immunology*
  • Gene Expression
  • Genes, Reporter
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / metabolism*
  • Herpesviridae Infections / pathology
  • Herpesviridae Infections / virology
  • Host-Pathogen Interactions* / immunology
  • Immunomodulation*
  • Immunophenotyping
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Mice
  • Mice, Transgenic

Substances

  • Biomarkers
  • Cytokines
  • Interleukin-10