Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis

PLoS One. 2013 Oct 14;8(10):e77634. doi: 10.1371/journal.pone.0077634. eCollection 2013.

Abstract

In multiple sclerosis (MS) autoaggressive T effector cells (Teff) are not efficiently controlled by regulatory T cells (Treg) but the underlying mechanisms are incompletely understood. Proinflammatory cytokines are key factors facilitating Teff activity in chronic inflammation. Here we investigated the influence of IL-6 on Treg sensitivity of Teff from therapy-naïve MS patients with or without active disease. Compared to healthy volunteers and independent of disease course CD4(+) and especially CD8(+) MS-Teff were insensitive against functional active Treg from healthy controls. This unresponsiveness was caused by accelerated production of IL-6, elevated IL-6 receptor expression and phosphorylation of protein kinase B (PKB)/c-Akt in MS-Teff. In a positive feedback loop, IL-6 itself induced its accelerated synthesis and enhanced phosphorylation of PKB/c-Akt that finally mediated Treg resistance. Furthermore, accelerated IL-6 release especially by CD8(+) Teff prevented control of surrounding Teff, described here as "bystander resistance". Blockade of IL-6 receptor signaling or direct inhibition of PKB/c-Akt phosphorylation restored Treg responsiveness of Teff and prevented bystander resistance. In Teff of healthy controls (HC) exogenous IL-6 also changed the kinetics of IL-6 production and induced Treg unresponsiveness. This modulation was only transient in Teff from healthy volunteers, whereas accelerated IL-6 production in MS-Teff maintained also in absence of IL-6. Hence, we showed that the kinetics of IL-6 production instead of elevated IL-6 levels defines the Teff responsiveness in early Treg-T cell communication in MS independent of their disease course and propose IL-6 and associated PKB/c-Akt activation as effective therapeutic targets for modulation of Teff activity in MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bystander Effect / immunology
  • Case-Control Studies
  • Clonal Anergy / immunology
  • Disease Progression
  • Feedback, Physiological
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Interleukin-6 / biosynthesis*
  • Kinetics
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology
  • Receptors, Interleukin-6 / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Up-Regulation
  • Young Adult

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL6 protein, human
  • Interleukin-6
  • Receptors, Interleukin-6

Grant support

Financial support was provided by the Transregio 128 (project A9 and B4) and by the Competence Network for Multiple Sclerosis, funded by the Federal Ministry of Education and Research (BMBF), FKZ 01GI0917 to H.J. and H.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.