IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy

Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2R alpha. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2R beta gamma, IL-15 does not bind IL-2R alpha and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2R alpha. Mechanistically, IL-2R alpha sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2R alpha endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2R alpha expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies.