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Defining the homeostatic mechanisms that support the diverse pool of peripheral regula-tory T (T reg) cells in lymphoid and nonlym-phoid sites is critical for developing effective strategies to manipulate T reg cell activity to promote allograft tolerance and treat autoim-munity, chronic infection, and cancer. Like con-ventional CD4+Foxp3 helper T cells, T reg cells are phenotypically and functionally heteroge-neous, with distinct populations associated with different tissue sites and inflammatory conditions (Campbell and Koch, 2011; Cretney et al., 2013). However, despite the considerable body of liter-ature highlighting the specialization of T reg cell subsets, the homeostatic mechanisms that main-tain such complexity remain poorly understood. As a population, T reg cells undergo rapid homeostatic proliferation in vivo (Fisson et al., 2003), which is thought to be due to their high degree of self-reactivity and their constitutive expression of the high-affinity IL-2 receptor component CD25, which signals through phos-phorylation of the transcription factor Stat5 (Hsieh et al., 2004; Setoguchi et al., 2005). In the steady state, IL-2 is produced by activated CD4+CD25+Foxp3 T cells and is thought to act in a paracrine fashion to link the size of the T reg cell compartment to the number of these activated T cells (Setoguchi et al., 2005), thereby ensuring that autoimmunity and inflammatory diseases do not develop as a result of uncon-trolled T cell activation. The importance of IL-2 in controlling T reg cell function in the periph-ery is indicated by the lymphoproliferative dis-ease that develops in mice deficient for IL-2 or its receptor (Sadlack et al., 1993; Willerford et al., 1995), and IL-2 is thought to control T reg cell homeostasis through regulation of genes involved in cell proliferation, metabolism, and apoptosis (Fontenot et al., 2005a). However, mice deficient in either IL-2 or CD25 contain near-normal numbers of T reg cells that are functionally suppressive in vitro, indicating that the role of IL-2 in controlling T reg cell abun-dance and activity is more complicated tha