A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells

Abstract

The IL-2/IL-2R interaction is important for development and peripheral homeostasis of T regulatory (Treg) cells. IL-2- and IL-2R-deficient mice are not completely devoid of Foxp3+ cells, but rather lack population of mature CD4+CD25+Foxp3high Treg cells and contain few immature CD4+CD25−Foxp3low T cells. Interestingly, common γ chain (γc) knockout mice have been shown to have a near complete absence of Foxp3+ Treg cells, including the immature CD25−Foxp3low subset. Therefore, other γc-cytokine(s) must be critically important during thymic development of CD4+CD25+Foxp3+ Treg cells apart from the IL-2. The present study was undertaken to determine whether the γc-cytokines IL-7 or IL-15 normally contribute to expression of Foxp3 and Treg cell production. These studies revealed that mice double deficient in IL-2Rβ and IL-7Rα contained a striking lack in the CD4+Foxp3+ population and the Treg cell defect recapitulated the γc knockout mice. In the absence of IL-7R signaling, IL-15/IL-15R interaction is dispensable for the production of CD4+CD25+Foxp3+ Treg cells, indicating that normal thymic Treg cell production likely depends on signaling through both IL-2 and IL-7 receptors. Selective thymic reconstitution of IL-2Rβ in mice double deficient in IL-2Rβ and IL-7Rα established that IL-2Rβ is dominant and sufficient to restore production of Treg cells. Furthermore, the survival of peripheral CD4+Foxp3low cells in IL-2Rβ−/− mice appears to depend upon IL-7R signaling. Collectively, these data indicate that IL-7R signaling contributes to Treg cell development and peripheral homeostasis.