Different dynamics of IL-15R activation following IL-15 cis- or trans-presentation

Interleukin (IL)-15 is a cytokine critical for the homeostasis and the function of NK cells, NK-T cells, and memory CD8(+) T cells. IL-15 signals are delivered through the IL-15R beta and the common gamma (gamma(c)) receptor chains. The third receptor chain, IL-15R alpha, confers specificity and high affinity for the cytokine. While IL-15 can activate with high affinity the trimeric receptor expressed by a target cell (cis-presentation), IL-15R alpha is also known to trans-present IL-15 with high affinity to target cells expressing the IL-15R beta/gamma(c) complex. In order to compare the IL-15 cis- and trans-presentation processes, and using a T cell line expressing both IL-15R alpha/beta/gamma(c) and IL-15R beta/gamma(c), we analyzed cell surface receptor chain down-modulation, cytokine internalization and signaling responses induced either with IL-15 (cis-presentation) or with RLI, a protein resulting from fusion between IL-15 and an extended IL-15R alpha sushi domain, that mimics trans-presentation. Whereas IL-15 bound with high affinity to IL-15R alpha/beta/gamma(c), RLI bound with a similar high affinity to IL-15R beta/gamma(c). The kinetics of cell surface IL-15R down-modulation were slower following RLI treatment than after IL-15 treatment, as were the kinetics of RLI internalization, which was slower than that of IL-15. IL-15 and RLI dose-dependently induced the activation of similar signaling pathways. However, the kinetics and duration of these activations were markedly different, RLI-induced signaling, being slower, but more prolonged than that induced by IL-15, although the final proliferative responses at 48 h were similar. These findings collectively indicate that IL-15 cis- and trans-presentation mechanisms lead to different dynamics of receptor activation and signal transduction, with cis-presentation inducing fast and transient responses, and trans-presentation inducing slower, more persistent ones. They provide clues for a better understanding of how IL-15 action is controlled, and how it plays a key role in the coordination between innate and adaptative immunity.