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-15R alpha -deficient (IL-15R alpha (-/-) -) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CDS' T cells. Surprisingly, IL-15R alpha (-/-) 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-15R alpha (-/-) mice. Normal mice reconstituted with IL-15R alpha (-/-) bone marrow cells also fail to exhibit bystander responses. Thus, CD8(+) T cell independent IL-15R alpha signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8(+) T cells proliferate in IL-15R alpha (-/-) mice after treatment with IL-15. Therefore, IL-15R alpha signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15R alpha supports memory phenotype CDS' T cell proliferation, and suggest novel mechanisms by which memory CD8(+) T cells are maintained in vivo.