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 effect 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 CD44highIL-2/15Rβhigh 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.