title: Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells.
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.
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. bettina.trinschek@unimedizin-mainz.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Trinschek
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. luessi@uni-mainz.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, University of Muenster, Schlossplatz 2, 48149 Muenster, Germany. catharina.gross@ukmuenster.de.
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Gross
authors.affiliation: Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, University of Muenster, Schlossplatz 2, 48149 Muenster, Germany. heinz.wiendl@ukmuenster.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. helmut.jonuleit@unimedizin-mainz.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology; D016899:Interferon-beta / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D016513:Mice, SCID; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; D016899:Interferon-beta; C502936:tocilizumab
keywords: T effector cells; Treg; diagnosis; immune regulation; multiple sclerosis; therapy