| Summary: | Single nucleotide polymorphisms (SNPs) in or near the <i>IL2RA</i> gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated <i>IL2RA</i> SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated <i>IL2RA</i> SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4<sup>+</sup> but not CD8<sup>+</sup> T cells. In CD4<sup>+</sup> T cells, carriers of the risk genotype had a reduced frequency of CD25<sup>+</sup> T<sub>FH</sub>1 cells (<i>p</i> = 0.001) and an increased frequency of CD25<sup>+</sup> recent thymic emigrant cells (<i>p</i> = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4<sup>+</sup> T cells (CD31<sup>−</sup>CD45RA<sup>+</sup>), CD39<sup>+</sup> T<sub>Reg</sub> cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated <i>IL2RA</i> SNPs on expression of CD25 in CD4<sup>+</sup> T cell subsets. Insight into the associations of MS-associated <i>IL2RA</i> SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS.
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