An essential role for the IL-2 receptor in Treg cell function

Regulatory T cells (Treg cells) that express the transcription factor Foxp3 restrain immune responses to self and foreign antigens1–3. Treg cells have abundant expression of the interleukin 2 receptor α-chain (IL-2Rα; CD25) but are unable to produce IL-2. IL-2 binds with low affinity to IL-2Rα or to heterodimers of the common γ-chain (γc; CD132) and IL-2Rβ (CD122), but receptor affinity increases ~1,000fold when these three subunits collectively interact with IL-2 (ref. 4). IL-2 and the transcription factor STAT5, a key target downstream of JAK kinases associated with IL-2R, are indispensable for inducing the expression of Foxp3 and differentiation of Treg cells in the thymus5–11. IL-2Rβ and γc are shared with the IL-15 receptor, whose signaling can also contribute to the induction of Foxp3 expression12. IL-2, in cooperation with the cytokine TGF-β, is also required for extrathymic Treg cell differentiation13. While the role of IL-2R signaling in the induction of Foxp3 expression and Treg cell differentiation in the thymus is well established, the importance of IL-2R expression in mature Treg cells is not well understood. Although deficiency in STAT5 abolishes Foxp3 expression, it can be restored by increased amounts of the anti-apoptotic molecule Bcl2. That finding raised the possibility that a chief role of IL-2 might be in the survival of differentiating Treg cells or their precursors14. It has also been reported that ablation of the pro-apoptotic protein Bim can rescue Treg cells or their precursors from apoptosis associated with deficiency in IL-2 or IL-2R and restore the number of Treg cells, but it does not prevent fatal autoimmunity15. However, a profound effect of congenital deficiency in IL-2, Bcl2 and Bim on the differentiation and selection of Treg cells and self-reactive effector T cells (Teff cells) has confounded interpretation of that observation. Antibody-mediated neutralization of IL-2 in adult mice that have undergone removal of the thymus reduces the number of Treg cells and Foxp3 expression in Treg cells16,17. Thus, IL-2 supports stability of the Treg cell lineage after differentiation18,19. However, expression of a transgene encoding IL-2Rβ exclusively in thymocytes has been reported to rescue Il2rb−/− mice from lethal autoimmune disease, which suggests that IL-2R expression is dispensable in peripheral Treg cells7,11. Thus, a role for IL-2R expression and signaling in peripheral Treg cells has remained uncertain. Hypothetically, a role for IL-2R in peripheral Treg cells could be threefold: guidance for Treg cells to sense their targets, which are activated self-reactive T cells that serve as a source of IL-2; Treg cell–mediated deprivation of IL-2 as a mechanism of suppression; and cell-intrinsic IL-2 signaling in differentiated Treg cells to support their maintenance, proliferation or function due to triggering of JAK–STAT5, PI3K–Akt or Ras–ERK signaling pathways. Previous studies have focused mainly on the induction or maintenance of Foxp3, while other aspects of IL-2R function have not been firmly established due to the aforementioned limitations. Despite their considerable reliance on IL-2 for the maintenance of Foxp3 expression, Treg cells are unable to produce IL-2. The reason for the inhibition of autologous activation of STAT5 in Treg cells and the potential biological importance of this IL-2-based Treg cell–Teff cell