Cutting Edge: Differential Fine-Tuning of IL-2- and IL-15- Dependent Functions by targeting their Common IL-2/15Rβ/γc Receptor

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their a receptor chains, IL-2R alpha and IL-15R alpha. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2R beta/gamma (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15- and IL-2-dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2R alpha receptor. Interestingly, due to the presence of IL-2R alpha, BiG had no impact on IL-2-dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.