Regulatory CD8+ T cells associated with erosion of immune surveillance in persistent virus infection suppress in vitro and have a reversible proliferative defect

J Immunol. 2013 Jul 1;191(1):312-22. doi: 10.4049/jimmunol.1201773. Epub 2013 Jun 3.


CD4(+) T cell help is critical for CD8(+) T cell memory and immune surveillance against persistent virus infections. Our recent data have showed the lack of CD4(+) T cells leads to the generation of an IL-10-producing CD8(+) T cell population during persistent murine γ-herpesvirus-68 (MHV-68) infection. IL-10 from these cells is partly responsible for erosion in immune surveillance, leading to spontaneous virus reactivation in lungs. In this study, we further characterized the generation, phenotype, and function of these IL-10-producing CD8(+) T cells by comparing with a newly identified IL-10-producing CD8(+) T cell population present during the acute stage of the infection. The IL-10-producing CD8(+) populations in acute and chronic stages differed in their requirement for CD4(+) T cell help, the dependence on IL-2/CD25 and CD40-CD40L pathways, and the ability to proliferate in vitro in response to anti-CD3 stimulation. IL-10-producing CD8(+) T cells in the chronic stage showed a distinct immunophenotypic profile, sharing partial overlap with the markers of previously reported regulatory CD8(+) T cells, and suppressed the proliferation of naive CD8(+) T cells. Notably, they retained the ability to produce effector cytokines and cytotoxic activity. In addition, the proliferative defect of the cells could be restored by addition of exogenous IL-2 or blockade of IL-10. These data suggest that the IL-10-producing CD8(+) T cells arising in chronic MHV-68 infection in the absence of CD4(+) T cell help belong to a subset of CD8(+) regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation*
  • Gammaherpesvirinae / immunology
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / pathology
  • Herpesviridae Infections / virology
  • Immune Tolerance
  • Immunologic Surveillance*
  • Interleukin-10 / biosynthesis
  • Lymphocyte Activation / immunology*
  • Lymphocyte Depletion
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NIH 3T3 Cells
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • T-Lymphocytes, Regulatory / virology


  • IL10 protein, mouse
  • Interleukin-10