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Different dynamics of IL-15R activation following IL-15 cis- or trans-presentation
Harmonie Perdreau1, Erwan Mortier, Grégory Bouchaud
1INSERM UMR 892, Centre de Recherche en Cancérologie Nantes/Angers, Groupe de Recherche Cytokines et Récepteurs en Immuno-Cancérologie, Nantes, France.
Insights
Interleukin-15 (IL-15) cis-presentation triggers rapid, transient immune cell signaling, while trans-presentation elicits slower, sustained responses. This difference in cytokine dynamics impacts immune coordination.
Area of Science:
- Immunology
- Cellular Biology
- Molecular Signaling
Background:
- Interleukin-15 (IL-15) is crucial for immune cell homeostasis and function, including NK cells, NK-T cells, and memory CD8+ T cells.
- IL-15 signaling relies on specific receptor chains (IL-15Rα, IL-15Rβ, and common γ chain γ(c)).
- IL-15 can be presented in cis (on the same cell) or trans (on a different cell) to activate target cells.
Purpose of the Study:
- To compare the distinct mechanisms of IL-15 cis- and trans-presentation.
- To analyze the downstream effects on receptor modulation, cytokine internalization, and signaling pathways.
- To elucidate how these presentation forms differentially regulate immune cell responses.
Main Methods:
- Utilized a T cell line expressing both IL-15 receptor complexes (IL-15Rα/β/γ(c) and IL-15Rβ/γ(c)).
- Compared responses induced by IL-15 (cis-presentation) versus RLI (a fusion protein mimicking trans-presentation).
- Assessed cell surface receptor down-modulation, cytokine internalization kinetics, and signaling pathway activation.
Main Results:
- Both IL-15 and RLI bound with high affinity to their respective receptor complexes.
- RLI treatment resulted in slower receptor down-modulation and internalization kinetics compared to IL-15.
- While both induced similar signaling pathways, RLI promoted slower, more prolonged signaling activation than IL-15, despite similar final proliferation.
Conclusions:
- IL-15 cis-presentation leads to rapid, transient signaling responses.
- IL-15 trans-presentation results in slower, more persistent signaling dynamics.
- These distinct signaling kinetics provide insights into IL-15's role in coordinating innate and adaptive immunity.
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.
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