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

Nat Commun. 2014 Oct 3:5:5056. doi: 10.1038/ncomms6056.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Flow Cytometry
  • Genome-Wide Association Study
  • Genotype
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
  • Healthy Volunteers
  • Humans
  • Interleukin-2 / metabolism
  • Interleukin-2 Receptor alpha Subunit / genetics*
  • Leukocytes, Mononuclear / cytology
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • Phosphorylation
  • Polymorphism, Genetic
  • STAT5 Transcription Factor / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes, Helper-Inducer / cytology


  • IL2RA protein, human
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • STAT5 Transcription Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor