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

• Verfasst von: Trinschek, Bettina [VerfasserIn]
• Verfasst von: Lüssi, Felix [VerfasserIn]
• Verfasst von: Haas, Jürgen [VerfasserIn]
• Verfasst von: Wildemann, Brigitte [VerfasserIn]
• Verfasst von: Zipp, Frauke [VerfasserIn]
• Verfasst von: Wiendl, Heinz [VerfasserIn]
• Verfasst von: Becker, Christian [VerfasserIn]
• Verfasst von: Jonuleit, Helmut [VerfasserIn]
• Titel: Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis
• Verf.angabe: Bettina Trinschek, Felix Lüssi, Jürgen Haas, Brigitte Wildemann, Frauke Zipp, Heinz Wiendl, Christian Becker, Helmut Jonuleit
• E-Jahr: 2013
• Jahr: October 14, 2013
• Umfang: 14 S.
• Fussnoten: Gesehen am 10.02.2022
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2013
• Band/Heft Quelle: 8(2013), 10, Artikel-ID e77634, Seite 1-14
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0077634
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: B cells
• Sach-SW: Cytokines
• Sach-SW: Cytotoxic T cells
• Sach-SW: Flow cytometry
• Sach-SW: Immune cells
• Sach-SW: Multiple sclerosis
• Sach-SW: Regulatory T cells
• Sach-SW: T cells
• K10plus-PPN: 178924174X

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.