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Authors: Trinschek, Bettina
Lüssi, Felix
Haas, Jürgen
Wildemann, Brigitte
Zipp, Frauke
Wiendl, Heinz
Becker, Christian
Jonuleit, Helmut
Title: Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis
Online publication date: 10-Oct-2022
Year of first publication: 2013
Language: english
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.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Plos one
Pages or article number: e77634
Publisher: PLoS
Publisher place: Lawrence, Kan.
Issue date: 2013
ISSN: 1932-6203
Publisher URL:
Publisher DOI: 10.1371/journal.pone.0077634
Appears in collections:DFG-OA-Publizieren (2012 - 2017)

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