IL-15 and IL-2 oppositely regulate expression of the chemokine receptor CX3CR1

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Abstract
The chemokine receptor CX3CR1 (CX3C chemokine receptor 1) is expressed in mouse blood on natural killer (NK) cells and on monocytes. Because interleukin-15 (IL-15) is an essential cytokine for NK cell development and maintenance, we hypothesized that it may induce CX3CR1 expression on this cell type. In contrast, we found that in primary mouse bone marrow-derived NK cells IL-15 specifically inhibited CX3CR1 protein and mRNA accumulation, whereas the related cytokine IL-2 did not inhibit but instead increased CX3CR1 expression. Consistent with this finding, intravenous injection of a single dose of recombinant IL-15 into C57BL/6 mice decreased steady-state CX3CR1 levels 24 hours after injection in freshly isolated peripheral blood mononuclear cells (PBMCs), splenocytes, and bone marrow cells, and treatment of mouse PBMCs with IL-15 in vitro inhibited CX3CL1 (ligand for CX3CR1)-induced chemotaxis. These data suggest that IL-15 may be a negative regulator of innate immunity by inhibiting CX3CR1 expression. These data also suggest that IL-15 inhibition of CX3CR1 may subvert potential cell immunotherapy strategies in which IL-15 is used to expand NK cell populations in vivo or ex vivo. Finally, our results provide additional evidence for differential signaling by IL-2 and IL-15, despite usage of common βγc receptor chains. (Blood. 2003;102:3494-3503)