A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells

The IL-2/IL-2R interaction is important for development and peripheral homeostasis of T regulatory (T-reg) cells. IL-2- and IL-2R-deficient mice are not completely devoid of Foxp3(+) cells, but rather lack population of mature CD4(+)CD25(+)Foxp3(high) T-reg cells and contain few immature CD4(+)CD25(-)Foxp(low) T cells. Interestingly, common gamma chain (gamma c) knockout mice have been shown to have a near complete absence of Foxp3(+) T-reg cells, including the immature CD25(-)Foxp(low) subset. Therefore, other gamma c-cytokine(s) must be critically important during thymic development of CD4(+)CD25(+)Foxp3(+) T-reg cells apart from the IL-2. The present study was undertaken to determine whether the gamma c-eytokines IL-7 or IL-15 normally contribute to expression of Foxp3 and T-reg cell production. These studies revealed that mice double deficient in IL-2R beta and IIL-7R alpha contained a striking lack in the CD4(+)Foxp3(+) population and the T-reg cell defect recapitulated the gamma c knockout mice. In the absence of IL-7R signaling, IL-15/IL-15R interaction is dispensable for the production of CD4(+)CD25(+)Foxp3(+) T-reg cells, indicating that normal thymic T-reg cell production likely depends on signaling through both IL-2 and IL-7 receptors. Selective thymic reconstitution of IL-2R beta in mice double deficient in IL-2R beta and IIL-7R alpha established that IL-2R beta is dominant and sufficient to restore production of T-reg cells. Furthermore, the survival of peripheral CD4(+)Foxp3(low) cells in IL-2R beta(-/-) mice appears to depend upon IL-7R signaling. Collectively, these data indicate that IL-7R signaling contributes to T-reg cell development and peripheral homeostasis.