title: Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis.
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.
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Trinschek
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.forename: Felix
authors.initials: F
authors.lastname: Lüssi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000328:Adult; D024201:Bystander Effect / Q000276:immunology; D016022:Case-Control Studies; D017635:Clonal Anergy / Q000276:immunology; D018450:Disease Progression; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6