Function of the IL-2R for thymic and peripheral CD4⁺CD25 ⁺ Foxp3⁺ T regulatory cells

IL-2 contributes to the production, function, and homeostasis of CD4 ⁺CD25⁺ T_reg cells. However, it remains uncertain whether IL-2 is essential for the development of T_reg cells in the thymus, their homeostasis in the periphery, or both. The present study was undertaken to investigate the contribution of IL-2 during thymic T _reg cell development and its maintenance in peripheral immune tissue. Relying on genetic mouse models where IL-2R signaling was either completely blocked or selectively inhibited in peripheral CD4⁺CD25⁺ T_reg cells, we show that the IL-2/IL-2R interaction is active in the thymus at the earliest stage of the development of T_reg cells to promote their expansion and to up-regulate Foxp3 and CD25 to normal levels. Furthermore, CD4⁺CD25⁺Foxp3⁺ T_reg cells with impaired IL-2-induced signaling persist in the periphery and control autoimmunity without constant thymic output. These peripheral T_reg cells with poor responsiveness to IL-2 exhibited slower growth and extended survival in vivo, somewhat lower suppressive activity, and poor IL-2-dependent survival in vitro. Mixed thymic and bone marrow chimeric mice showed that wild-type-derived T_reg cells were substantially more effective in populating peripheral immune tissue than T_reg cells with impaired IL-2 signaling. Collectively, these data support the notion that normally IL-2 is a dominant mechanism controlling the number of thymic and peripheral T _reg cells.