The Cytokine Receptor IL-7Rα Impairs IL-2 Receptor Signaling and Constrains the In Vitro Differentiation of Foxp3+ Treg Cells

IL-7 receptor signaling is essential for the generation and maintenance of conven-tional T cells. Immunosuppressive Foxp3(+) Treg cells, however, express uniquely low amounts of the IL-7-proprietary IL-7R alpha so that they are impaired in IL-7 signaling. Because Treg cells depend on IL-2, the loss of IL-7R alpha has been consid-ered irrelevant for Treg cells. In contrast, here, we report that IL-7R alpha downregu-lation is necessary to maximize IL-2R signaling. Although IL-7R alpha overexpression promoted IL-7 signaling, unexpectedly, IL-2 signaling was suppressed in the same cells. Mechanistically, we found that gc, which is a receptor subunit shared by IL-7R and IL-2R, directly binds and pre-associates with IL-7R alpha, thus limiting its availability for IL-2R binding. Consequently, overexpression of signaling-defi-cient, tailless IL-7R alpha proteins inhibited IL-2R signaling, demonstrating that IL-7R alpha sequesters gc and suppresses IL-2R signaling by extracellular interactions. Collectively, these results reveal a previously unappreciated regulatory mecha-nism of IL-2 receptor signaling that is governed by IL-7R alpha abundance.