Trans -endocytosis of intact IL-15Rα–IL-15 complex from presenting cells into NK cells favors signaling for proliferation

Autor: Michael J. Hollander, Eric O. Long, Sumati Rajagopalan, Erik L. Snapp, Olga M. Anton, Thomas A. Waldmann, K. Christopher Garcia, David W. Dorward, Mary E. Peterson, Javier Traba, Gunjan Arora
Rok vydání: 2019
Předmět:
Zdroj: Proc Natl Acad Sci U S A
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.1911678117
Popis: 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(c)) chain heterodimer of the IL-2 receptor through trans-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 trans-endocytosis and contribute to the phosphorylation of ribosomal protein S6 and NK cell proliferation. NK cell interaction with soluble or surface-bound IL-15Rα–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-15Rα–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-15Rα–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.
Databáze: OpenAIRE
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