Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells

Felix J. Hartmann, Mohsen Khademi, Jehan Aram, Sandra Ammann, Ingrid Kockum, Cris Constantinescu, Bruno Gran, Fredrik Piehl, Tomas Olsson, Laura Codarri () and Burkhard Becher ()
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Felix J. Hartmann: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland
Mohsen Khademi: Neuroimmunology Unit, Karolinska Institutet
Jehan Aram: Clinical Neurology, University of Nottingham
Sandra Ammann: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland
Ingrid Kockum: Neuroimmunology Unit, Karolinska Institutet
Cris Constantinescu: Clinical Neurology, University of Nottingham
Bruno Gran: Clinical Neurology, University of Nottingham
Fredrik Piehl: Neuroimmunology Unit, Karolinska Institutet
Tomas Olsson: Neuroimmunology Unit, Karolinska Institutet
Laura Codarri: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland
Burkhard Becher: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich 8052, Switzerland

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6056

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