Self-Sustained Resistance to Suppression of CD8+ Teff Cells at the Site of Autoimmune Inflammation Can Be Reversed by Tumor Necrosis Factor and Interferon-γ Blockade

Arthritis Rheumatol. 2016 Jan;68(1):229-36. doi: 10.1002/art.39418.

Abstract

Objective: Resistance of Teff cells to Treg cell-mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). However, unanswered questions are whether this resistant phenotype is self-sustained and whether CD8+ and CD4+ Teff cells share the same mechanism of resistance to suppression. We undertook this study to investigate intrinsic resistance of CD8+ Teff cells to suppression and to determine how this can be targeted therapeutically.

Methods: CD8+ or CD4+ Teff cells were cultured with or without antigen-presenting cells (APCs) in Treg cell-dependent and -independent suppression assays. Synovial fluid (SF)-derived Teff cells were crosscultured with peripheral blood (PB) Treg cells from JIA patients or healthy controls. Tumor necrosis factor (TNF) or interferon-γ (IFNγ) blocking agents were used to restore Teff cell responsiveness to suppression.

Results: Suppression of cell proliferation and cytokine production in CD8+ Teff cells from the SF of JIA patients was severely impaired compared to that in CD8+ Teff cells from the PB of JIA patients, regardless of the presence of APCs and CD4+ Teff cells. Similar to CD4+ Teff cells, impaired suppression of CD8+ Teff cells was shown to be an intrinsic feature of this cell population. While TNF blockade restored both CD8+ and CD4+ Teff cell susceptibility to suppression, autocrine release of IFNγ selectively sustained CD8+ Teff cell resistance, which could be relieved by IFNγ blockade.

Conclusion: Unlike CD4+ Teff cells, resistance of CD8+ Teff cells to suppression at the site of autoimmune inflammation is maintained by autocrine release of IFNγ, and blockade of IFNγ restores CD8+ Teff cell responsiveness to suppression. These findings indicate a potential therapeutic value of blocking IFNγ to restore immune regulation in JIA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antigen-Presenting Cells
  • Arthritis, Juvenile / immunology*
  • Autoimmune Diseases
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Cell Proliferation
  • Child
  • Cytokines / immunology*
  • Female
  • Flow Cytometry
  • Humans
  • Inflammation
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / immunology*
  • Interleukin-10 / immunology
  • Interleukin-17 / immunology
  • Interleukin-6 / immunology
  • Male
  • Synovial Fluid / cytology
  • T-Lymphocytes, Regulatory
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • Cytokines
  • IL10 protein, human
  • IL6 protein, human
  • Interleukin-17
  • Interleukin-6
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma