<i>Trans</i>-endocytosis of intact IL-15Rα–IL-15 complex from presenting cells into NK cells favors signaling for proliferation
- Anton, Olga M. 25
- Peterson, Mary E. 2
- Hollander, Michael J. 1
- Dorward, David W. 6
- Arora, Gunjan 2
- Traba, Javier 4
- Rajagopalan, Sumati 2
- Snapp, Erik L. 3
- Garcia, K. Christopher 1
- Waldmann, Thomas A. 5
- Long, Eric O. 2
- 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;
- 2 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892;
- 3 Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147
- 4 Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
- 5 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
- 6 Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
ISSN: 0027-8424, 1091-6490
Argitalpen urtea: 2019
Alea: 117
Zenbakia: 1
Orrialdeak: 522-531
Mota: Artikulua
Beste argitalpen batzuk: Proceedings of the National Academy of Sciences
Laburpena
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 (γc) 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.
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