Open Access

ARTICLE

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

Harmonie Perdreau^1,2, Erwan Mortier^1,2, Grégory Bouchaud^1,2, Véronique Solé^1,2, Yvan Boublik³, Ariane Plet^1,2,*, Yannick Jacques^1,2,*

1 Inserm, UMR 892, Centre de Recherche en Cancérologie Nantes/Angers, Groupe de Recherche Cytokines et Récepteurs en Immuno-Cancérologie, Nantes, France
2 Université de Nantes, IFR 26, Nantes, France
3 CNRS, UMR 5237, Centre de Recherche en Biochimie Macromoléculaire, Montpellier, France

* Corresponding Author: E. Mortier, Inserm,

European Cytokine Network 2010, 21(4), 297-307. https://doi.org/10.1684/ecn.2010.0207

Accepted 30 July 2010;

Abstract

Interleukin (IL)-15 is a cytokine critical for the homeostasis and the function of NK cells, NK-Tcells, and memory CD8+ T cells. IL-15 signals are delivered through the IL-15Rβ and the commonγ (γ_c) receptorchains. The third receptor chain, IL-15Rα, confers specificity and high affinity for the cytokine. While IL-15 canactivate with high affinity the trimeric receptor expressed by a target cell (cis-presentation), IL-15Rα is alsoknown to trans-present IL-15 with high affinity to target cells expressing the IL-15Rβ/γ_c complex. In order tocompare the IL-15 cis- and trans-presentation processes, and using a T cell line expressing both IL-15Rα/β/γ_c andIL-15Rβ/γ_c, we analyzed cell surface receptor chain down-modulation, cytokine internalization and signalingresponses induced either with IL-15 (cis-presentation) or with RLI, a protein resulting from fusion betweenIL-15 and an extended IL-15Rα sushi domain, that mimics trans-presentation. Whereas IL-15 bound with highaffinity to IL-15Rα/β/γ_c, RLI bound with a similar high affinity to IL-15Rβ/γ_c. The kinetics of cell surfaceIL-15R down-modulation were slower following RLI treatment than after IL-15 treatment, as were the kineticsof RLI internalization, which was slower than that of IL-15. IL-15 and RLI dose-dependently induced the activa-tion of similar signaling pathways. However, the kinetics and duration of these activations were markedly differ-ent, RLI-induced signaling, being slower, but more prolonged than that induced by IL-15, although the finalproliferative 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, withcis-presentation inducing fast and transient responses, and trans-presentation inducing slower, more persistentones. They provide clues for a better understanding of how IL-15 action is controlled, and how it plays a keyrole in the coordination between innate and adaptative immunity.

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