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.