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

Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (T-H) 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 T-H cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human T-H 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 T-H cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive T-H cells and their propensity to develop into GM-CSF-producing memory T-H cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of T-H cells in MS.