Abstract
Interleukin-15 (IL-15) is crucial for the generation of multiple lymphocyte subsets (natural killer (NK), NK-T cells, and memory CD8 T cells), and transpresentation of IL-15 by monocytes and dendritic cells has been suggested to be the dominant activating process of these lymphocytes. We have previously shown that a natural soluble form of IL-15R alpha chain corresponding to the entire extracellular domain of IL-15R alpha behaves as a high affinity IL-15 antagonist. In sharp contrast with this finding, we demonstrate in this report that a recombinant, soluble sushi domain of IL-15R alpha, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R beta/gamma heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R alpha/beta/gamma membrane receptor. Our results suggest that, if naturally produced, such soluble sushi domains might be involved in the IL-15 transpresentation mechanism. Fusion proteins (RLI and ILR), in which IL-15 and IL-15R alpha-sushi are attached by a flexible linker, are even more potent than the combination of IL-15 plus sIL-15R alpha-sushi. After binding to IL-15R beta/gamma, RLI is internalized and induces a biological response very similar to the IL-15 high affinity response. Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.
Highlights
IL-153 is a cytokine that was originally described, like IL-2, as a T cell growth factor [1]
IL-15R␣ Binding to IL-15 Is Mainly Due to the Sushi Domain—In a previous study [28], we have shown that removal of the sushi domain encoded by exon 2 of IL-15R␣ resulted in a complete abrogation of IL-15 binding to membrane anchored IL-15R␣, suggesting that the sushi domain was indispensable for binding
This sIL-15R␣-sushi bound IL-15 with a lower affinity (Fig. 1C). These results indicate that the sushi domain is responsible for most of the binding affinity of IL-15 but that it does not fully reconstitute the high affinity binding displayed by the full-length extracellular domain
Summary
IL-153 is a cytokine that was originally described, like IL-2, as a T cell growth factor [1]. A sIL-15R␣1⁄7IL-2 fusion protein produced in Chinese hamster ovary cells and consisting of the entire IL-15R␣ extracellular domain linked to a molecule of human IL-2 (used as a tag for purification) bound IL-15 with high affinity
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