title: Different dynamics of IL-15R activation following IL-15 cis- or trans-presentation.
abstract: 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-15Rβ and the common γ (γ(c)) receptor chains. The third receptor chain, IL-15Rα, 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-15Rα is also known to trans-present IL-15 with high affinity to target cells expressing the IL-15Rβ/γ(c) complex. In order to compare the IL-15 cis- and trans-presentation processes, and using a T cell line expressing both IL-15Rα/β/γ(c) and IL-15Rβ/γ(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-15Rα sushi domain, that mimics trans-presentation. Whereas IL-15 bound with high affinity to IL-15Rα/β/γ(c), RLI bound with a similar high affinity to IL-15Rβ/γ(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.
authors.affiliation: INSERM UMR 892, Centre de Recherche en Cancérologie Nantes/Angers, Groupe de Recherche Cytokines et Récepteurs en Immuno-Cancérologie, Nantes, France.
authors.forename: Harmonie
authors.initials: H
authors.lastname: Perdreau
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
authors.forename: Grégory
authors.initials: G
authors.lastname: Bouchaud
authors.forename: Véronique
authors.initials: V
authors.lastname: Solé
authors.forename: Yvan
authors.initials: Y
authors.lastname: Boublik
authors.forename: Ariane
authors.initials: A
authors.lastname: Plet
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D053647:Receptors, Interleukin-15 / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins