Interleukin-2 Instructs Regulatory T Cell Heterogeneity in the Periphery

Abstract

Over 20 million Americans suffer from autoimmune disease with the incidence steadily increasing over the past twenty years. Perturbations in regulatory T cells (Tregs) have been shown to cause autoimmunity, which is a population that is essential to keep autoreactive T cells in check. Non-functional mutations in the IL-2 receptor (IL-2R) in humans cause autoimmune diseases, leading many to conclude that IL-2 provides an essential survival signal for Tregs. However, recent evidence indicates that this role for IL-2 is overly simplistic. The Treg pool is highly heterogeneous, with functionally distinct subsets that are affected asymmetrically by a loss of IL-2R signaling. Attempts to understand the role of peripheral IL-2 signaling in Tregs have been frustrated by its critical role in Treg development in thymus, whereby IL-2R signaling is essential to generate Tregs effective at maintaining T cell homeostasis and preventing lethal autoimmunity. Yet, the post-thymic role of IL-2 has critical therapeutic implications because any IL-2-based therapy needs to target Tregs in tissues where an effector response is ongoing. We use a mouse model of tamoxifen-induced, Treg-specific knockout of CD25 (IL2R?) which forms the high-affinity IL-2 receptor to study post-thymic Tregs after IL-2R signaling is ablated. Previous work with this model shows IL-2 has an unequivocal role in Treg survival as evidenced by Tregs that cannot survive past 15 weeks once they lose CD25. Yet prior to their disappearance, Tregs undergo significant changes in their subset distribution as well as in their metabolism. CD62Lhi cTregs are disproportionately affected by a loss of CD25 with a corresponding increase in the abundance of CD62Llo eTregs. Similarly, the mevalonate pathway, which is critical to generate cholesterol and other important cellular components, is altered in Tregs after loss of CD25. The work in this dissertation focuses on clarifying IL-2&rsquo;s regulation of Treg heterogeneity and metabolism so that its role in post-thymic Tregs can be capitalized on in our therapeutic approaches to autoimmunity.</p