Converting IL-15 to a superagonist by binding to soluble IL-15Rα

IL-15 is normally presented in vivo as a cell-associated cytokine bound to IL-15R alpha. We show here that the biological activity of soluble IL-15 is much improved after interaction with recombinant soluble IL-15R alpha; after injection, soluble IL-15/IL-15R alpha complexes rapidly induce strong and selective expansion of memory-phenotype CD8(+) cells and natural killer cells. These findings imply that binding of IL-15R alpha to IL-15 may create a conformational change that potentiates IL-15 recognition by the beta gamma(c) receptor on T cells. The enhancing effect of IL-15R alpha binding may explain why IL-15 normally functions as a cell-associated cytokine. Significantly, the results with IL-2, a soluble cytokine, are quite different; thus, IL-2 function is markedly inhibited by binding to soluble IL-2R alpha.