title: Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells.
abstract: Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (TH) cell differentiation are associated with risk of developing MS. However, the underlying mechanism by which these risk alleles influence MS susceptibility has remained elusive. Initiation of neuroinflammation in animal models of MS has been shown to be dependent on TH cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human TH cells with MS disease severity. GM-CSF is strongly induced by interleukin 2 (IL-2). We show that an MS-associated polymorphism in the IL-2 receptor alpha (IL2RA) gene specifically increases the frequency of GM-CSF-producing TH cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive TH cells and their propensity to develop into GM-CSF-producing memory TH cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of TH cells in MS.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Hartmann
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.affiliation: Clinical Neurology, Division of Clinical Neurosciences, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Jehan
authors.initials: J
authors.lastname: Aram
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ammann
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Clinical Neurology, Division of Clinical Neurosciences, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Cris
authors.initials: C
authors.lastname: Constantinescu
authors.affiliation: Clinical Neurology, Division of Clinical Neurosciences, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gran
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Codarri
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D049109:Cell Proliferation; D005434:Flow Cytometry; D055106:Genome-Wide Association Study; D005838:Genotype; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D064368:Healthy Volunteers; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor