Thymic IL-2R expression is sufficient for production of CD4+CD25+ Foxp3+ T regulatory cells (95.5)

Abstract

Abstract CD4+CD25+ FoxP3+ Treg cells critically depend on IL-2, but the contribution of IL-2 to development of Treg cells in the thymus versus controlling their homeostasis in the periphery is unresolved. We addressed this issue using models where IL-2R activity was blocked in the thymus and periphery or only in the periphery. We found that IL-2/IL-2R interaction is active and essential in the thymus by promoting Treg cell expansion and upregulation of Foxp3 and CD25 to normal levels. This thymic signal gave rise to peripheral Treg cells with impaired IL-2-dependent STAT5 activation, yet they persisted in the periphery and suppressed autoimmunity without continual thymic output. Thus, thymic IL-2R function represents one important aspect for Treg cell development. Peripheral Treg cells with impaired IL-2R signaling exhibited slower growth and death rates as assessed by BrdU uptake in vivo and their suppressive activity was slightly lower in vitro. Importantly, by following donor Treg cells in mixed thymic and bone marrow chimeric mice, we found that WT Treg cells dominated peripheral immune tissue compared to Treg cells with impaired peripheral IL-2 signaling. Thus, IL-2 is a dominant mechanism controlling the number of thymic and peripheral Treg cells, although in a non-competitive setting, peripheral Treg cells with minimal IL-2R signaling persist and control autoimmunity. (Supported by the NIH)