Biology of IL-15 and therapeutic applications

Antigen specific memory CD8+ T cells and NK cells are cytolytic lymphocytes that kill infected host and transformed cells. By enhancing their expansion and effector functions, IL-15 is a major cytokine involved in increasing anti-tumor immune responses and the efficacy of vaccines. Both IL-15 and its high affinity receptor, IL-15Rα, are required for IL-15 signaling in vivo. While IL-2 and IL-15 share receptor subunits and some in vitro activities, they display different functions in vivo, IL-2 now appearing to selectively promote the expansion of regulatory T cells, and IL-15 to expand NK cells and rescue memory CD8+ T cells. Indeed, therapeutic trials have recently begun to take advantage of IL-15’s unique immuno-modulatory properties.

IL-15 shares with IL-2 the heterodimeric IL-15Rβ (CD122)/IL-15Rγ (CD132) receptor. Its specificity of action is conferred by its alpha chain, IL-15Rα (CD125). The high affinity of IL-15 for IL-15Rα allows IL-15 to act in trans-presentation: membrane-bound IL-15. IL-15Rα complex interacts and delivers IL-15 signal to cells expressing the CD122/CD132 receptor. Trans-presentation has been shown to be the dominant mechanism delivering IL-15 signal in vivo. Whereas IL-15 mRNA is expressed by a large number of tissues, detection of IL-15 protein is largely limited to monocytes and dendritic cells. This tight regulation is likely required owing to IL-15’s potent pro-inflammatory role. Indeed, IL-15 has been hypothesized to sit at the apex of a pro-inflammatory cytokine cascade which uncontrolled expression would result in the induction of inflammation and autoimmunity.

Deficiencies in IL-15/IL-15Rα signaling compromise the survival and function of CD8+ T cells and NK cells. On the other hand, excess IL-15/IL-15Rα signaling leads to marked expansions of the numbers of these cells and promotes leukemia. Thus, proper regulation of IL-15/IL-15Rα signaling to lymphocytes is critical for both optimal cytolytic immune responses as well as for preventing lymphoid malignancies. Improving our understanding of the regulation of IL-15/IL-15Rα signals and the mechanism(s) by which IL-15 and IL-15Rα support NK cells and memory CD8+ T cells should allow to optimize immune interventions in selected diseases (inflammation, autoimmunity, cancer) as well as treat certain types of leukemia and lymphoma.

Our research team is focused on deciphering IL-15 underpinning molecular mechanisms of regulation, and on determining whether altered expression of IL-15 could underlie aberrant cell activation in the context of inflammation and cancer. Thus, IL-15 represents an interesting pharmacological and therapeutic target in the treatment of certain cancers and inflammatory diseases. Based on different observations depicting IL-15 interaction with its different receptor chains, we have generated, in the laboratory, original IL-15-derived molecules presenting either agonistic or antagonistic activity. We are currently evaluating their potent activity in different models of cancer and inflammation. Our goal is to capitalize on our specificity to strengthen the link between basic understanding of molecular mechanisms and in vivo transfer of original and innovative IL-15-derived drugs.