T Cell–Independent Interleukin 15rα Signals Are Required for Bystander Proliferation

Cytokine driven or “bystander” proliferation of T cells occurs in vivo independently of major histocompatibility complex–T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Rα–deficient (IL-15Rα^−/−) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8⁺ T cells. Surprisingly, IL-15Rα^−/− CD8⁺ T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8⁺ T cells fail to proliferate in IL-15Rα^−/− mice. Normal mice reconstituted with IL-15Rα^−/− bone marrow cells also fail to exhibit bystander responses. Thus, CD8⁺ T cell independent IL-15Rα signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8⁺ T cells proliferate in IL-15Rα^−/− mice after treatment with IL-15. Therefore, IL-15Rα signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Rα supports memory phenotype CD8⁺ T cell proliferation, and suggest novel mechanisms by which memory CD8⁺ T cells are maintained in vivo.