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
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7927
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/3.0/
Journal:	Plos one 8 10
Pages or article number:	e77634
Publisher:	PLoS
Publisher place:	Lawrence, Kan.
Issue date:	2013
ISSN:	1932-6203
Publisher URL:	http://dx.doi.org/10.1371/journal.pone.0077634
Publisher DOI:	10.1371/journal.pone.0077634
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)