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Trans-endocytosis of intact IL-15R?-IL-15 complex from presenting cells into NK cells favors signaling for proliferation.


ABSTRACT: Interleukin 15 (IL-15) is an essential cytokine for the survival and proliferation of natural killer (NK) cells. IL-15 activates signaling by the ? and common ? (?c) chain heterodimer of the IL-2 receptor through trans-presentation by cells expressing IL-15 bound to the ? chain of the IL-15 receptor (IL-15R?). We show here that membrane-associated IL-15R?-IL-15 complexes are transferred from presenting cells to NK cells through trans-endocytosis and contribute to the phosphorylation of ribosomal protein S6 and NK cell proliferation. NK cell interaction with soluble or surface-bound IL-15R?-IL-15 complex resulted in Stat5 phosphorylation and NK cell survival at a concentration or density of the complex much lower than required to stimulate S6 phosphorylation. Despite this efficient response, Stat5 phosphorylation was reduced after inhibition of metalloprotease-induced IL-15R?-IL-15 shedding from trans-presenting cells, whereas S6 phosphorylation was unaffected. Conversely, inhibition of trans-endocytosis by silencing of the small GTPase TC21 or expression of a dominant-negative TC21 reduced S6 phosphorylation but not Stat5 phosphorylation. Thus, trans-endocytosis of membrane-associated IL-15R?-IL-15 provides a mode of regulating NK cells that is not afforded to IL-2 and is distinct from activation by soluble IL-15. These results may explain the strict IL-15 dependence of NK cells and illustrate how the cellular compartment in which receptor-ligand interaction occurs can influence functional outcome.

SUBMITTER: Anton OM 

PROVIDER: S-EPMC6955382 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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<i>Trans</i>-endocytosis of intact IL-15Rα-IL-15 complex from presenting cells into NK cells favors signaling for proliferation.

Anton Olga M OM   Peterson Mary E ME   Hollander Michael J MJ   Dorward David W DW   Arora Gunjan G   Traba Javier J   Rajagopalan Sumati S   Snapp Erik L EL   Garcia K Christopher KC   Waldmann Thomas A TA   Long Eric O EO  

Proceedings of the National Academy of Sciences of the United States of America 20191223 1


Interleukin 15 (IL-15) is an essential cytokine for the survival and proliferation of natural killer (NK) cells. IL-15 activates signaling by the β and common γ (γ<sub>c</sub>) chain heterodimer of the IL-2 receptor through <i>trans</i>-presentation by cells expressing IL-15 bound to the α chain of the IL-15 receptor (IL-15Rα). We show here that membrane-associated IL-15Rα-IL-15 complexes are transferred from presenting cells to NK cells through <i>trans</i>-endocytosis and contribute to the pho  ...[more]

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