IL-2 and IL-15 drive intrathymic differentiation of functionally distinct regulatory T lymphocyte-clusters

Intrathymic development of Foxp3-expressing regulatory T lymphocytes (Treg) depends on signals from the TCR, cytokine-receptors, and other cell-surface receptors. The cytokines IL-2 and IL-15 have been suggested to quantitatively modulate Treg-development. However, recent evidence showed that very large proportions of thymic Treg are cells that had migrated from the periphery back to the thymus. It remained therefore unclear if IL-2 and IL-15 quantitatively control the development of Treg. Moreover, these cytokines may also contribute to the differentiation of functionally distinct Treg subsets. Using an experimental setting in which we unambiguously distinguish newly developing from recirculating Treg, we here address the quantitative and qualitative roles of IL-2 and IL-15 in Treg-development, selection, and differentiation. Our results definitively demonstrate that in absence of IL-2 or IL-15 the thymus produces substantially less Treg. Importantly, IL-2 and IL-15 drive the differentiation of transcriptionally and phenotypically distinct Treg clusters, the number of which is substantially higher than previously appreciated. These cytokines also differentially modulate the TCR-repertoire expressed by newly developing Treg. Adoptive transfer of Treg from wt, IL-2- or IL-15-deficient animals into Treg-deficient new-born Scurfy mice, revealed differences in the in vivo function of these cells. Combined, our results indicate that IL-2 and IL-15 drive the development of functionally complementary Treg clusters.