The Abundance and Availability of Cytokine Receptor IL-2R beta (CD122) Constrain the Lymphopenia-Induced Homeostatic Proliferation of Naive CD4 T Cells

Lymphopenia-induced homeostatic proliferation (LIP) is a critical mechanism for restoring T cell immunity upon lymphodepleting insults or infections. LIP is primarily driven by homeostatic cytokines, such as IL-7 and IL-15, but not all T cells respond with the same efficiency to homeostatic proliferative cues. Although CD8 T cells vigorously proliferate under lymphopenic conditions, naive CD4 T cells are substantially impaired in their response to homeostatic cytokines, and they fail to fully expand. In this study, we show that the availability of IL-2R beta (CD122), which is a receptor subunit shared by IL-2 and IL-15, affects both the cytokine responsiveness and the LIP of naive CD4 T cells in the mouse. The enumeration of surface IL-2R beta molecules on murine naive CD4 and naive CD8 T cells revealed a 5-fold difference in IL-2R beta abundance. Notably, it was the limited availability of IL-2R beta that impaired CD4 T cell responsiveness to IL-15 and suppressed their LIP. As such, forced IL-2R beta expression on CD4 T cells by transgenesis bestowed IL-15 responsiveness onto naive CD4 T cells, which thus acquired the ability to undergo robust LIP. Collectively, these results identify IL-2R beta availability as a new regulatory mechanism to control cytokine responsiveness and the homeostatic proliferation of murine CD4 T cells.