Evidence of a novel IL-2/15Rβ-targeted cytokine involved in homeostatic proliferation of memory CD8⁺ T cells

The homeostasis of memory CD8⁺ T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of Memory CD8⁺ T cells, while IL-2 suppresses their division in vivo. This inhibitory efect of IL-2 appears to occur indirectly, through other cell populations including CD25⁺CD4⁺ T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8⁺ T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44^highIL-2/ 15Rβ^high CD8⁺ T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rβ signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8⁺ T cells, although the only cytokines known to act through IL-2/15Rβ are IL-2 and IL-15; and 4) the expression of IL-2/15Rβ molecules on memory CD8⁺ T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8⁺ T cell division by an IL-15-independent but by an IL-2/15Rβ-dependent mechanism, suggesting the existence of a novel IL-2/15Rβ-utilizing cytokine that acts directly on memory CD8⁺ T cells to promote cell division.