title: Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4(+) T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro. Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases.
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Janssens
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Brussels, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Somers
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium; Revalidatie & MS-Centrum, Boemerangstraat 2, 3900 Overpelt, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Van Wijmeersch
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
authors.forename: Helena
authors.initials: H
authors.lastname: Slaets
authors.affiliation: Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium. Electronic address: niels.hellings@uhasselt.be.
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016022:Case-Control Studies; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000276:immunology* / Q000494:pharmacology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D015850:Interleukin-6; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit
keywords: Leukemia inhibitory factor; Multiple sclerosis; Regulatory T cells; Therapeutics