Although the interleukin-2 (IL-2)/IL-2R signaling pathway has been the focus of numerous studies, certain aspects of its molecular regulation are not well characterized, especially in non-T cells, and a more complete understanding of the pathway is necessary to discern the functional basis of the genetic association between the IL-2-IL-21 and IL-2RA/CD25 gene regions and T1D in humans. Genetic variation in these regions may promote T1D susceptibility by influencing transcription and/or splicing and, hence, IL-2 and IL-2RA/CD25 expression at the protein level in different immune cell subsets; thus, there is a need to establish links between the genetic variation and immune cell phenotypes and functions in humans, which can be further investigated and validated in mouse models. The detection and characterization of genetically determined immunophenotypes should aid in elucidating disease mechanisms and may enable future monitoring of disease initiation and progression in prediabetic subjects and of responses to therapeutic intervention.