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Int. J. Mol. Sci. 2015, 16(7), 16330-16346; doi:10.3390/ijms160716330

Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells

1
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany
2
Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany
3
Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, University of Muenster, Schlossplatz 2, 48149 Muenster, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Christoph Kleinschnitz
Received: 11 May 2015 / Revised: 10 June 2015 / Accepted: 6 July 2015 / Published: 17 July 2015
(This article belongs to the Special Issue Advances in Multiple Sclerosis)
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Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by imbalanced immune regulatory networks, and MS patient-derived T effector cells are inefficiently suppressed through regulatory T cells (Treg), a phenomenon known as Treg resistance. In the current study we investigated T cell function in MS patients before and after interferon-beta therapy. We compared cytokine profile, responsiveness for Treg-mediated suppression ex vivo and evaluated reactivity of T cells in vivo using a humanized mouse model. We found that CD4+ and CD8+ T cells of therapy-naive MS patients were resistant to Treg-mediated suppression. Treg resistance is associated with an augmented IL-6 production, enhanced IL-6 receptor expression, and increased PKB/c-Akt phosphorylation. These parameters as well as responsiveness of T cells to Treg-mediated suppression were restored after interferon-beta therapy of MS patients. Following transfer into immunodeficient mice, MS T cells induced a lethal graft versus host disease (GvHD) and in contrast to T cells of healthy volunteers, this aggressive T cell response could not be controlled by Treg, but was abolished by anti-IL-6 receptor antibodies. However, magnitude and lethality of GvHD induced by MS T cells was significantly decreased after interferon-beta therapy and the reaction was prevented by Treg activation in vivo. Our data reveals that interferon-beta therapy improves the immunoregulation of autoaggressive T effector cells in MS patients by changing the IL-6 signal transduction pathway, thus restoring their sensitivity to Treg-mediated suppression. View Full-Text
Keywords: multiple sclerosis; therapy; diagnosis; immune regulation; T effector cells; Treg multiple sclerosis; therapy; diagnosis; immune regulation; T effector cells; Treg
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Trinschek, B.; Luessi, F.; Gross, C.C.; Wiendl, H.; Jonuleit, H. Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells. Int. J. Mol. Sci. 2015, 16, 16330-16346.

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