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

Anton, Olga M.; Peterson, Mary E.; Hollander, Michael J.; Dorward, David W.; Arora, Gunjan; Traba, Javier; Rajagopalan, Sumati; Snapp, Erik L.; Garcia, K. Christopher; Waldmann, Thomas A.; Long, Eric O.

doi:10.1073/PNAS.1911678117

<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;

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Revista:

Proceedings of the National Academy of Sciences

ISSN: 0027-8424, 1091-6490

Año de publicación: 2019

Volumen: 117

Número: 1

Páginas: 522-531

Tipo: Artículo

DOI: 10.1073/PNAS.1911678117 GOOGLE SCHOLAR Acceso abierto editor

Otras publicaciones en: Proceedings of the National Academy of Sciences

Resumen

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.

Referencias bibliográficas

10.1182/blood-2007-09-077438
10.1182/blood.V97.1.14
10.1038/nri2580
10.1073/pnas.92.2.377
10.4049/jimmunol.171.10.5085
10.1084/jem.191.5.771
10.1016/S1074-7613(00)80664-0
10.1084/jem.185.3.499
10.4049/jimmunol.174.3.1213
10.1016/S1074-7613(02)00429-6
10.1182/blood-2003-12-4187
10.1084/jem.20071913
10.1084/jem.20021836
10.1016/j.imlet.2009.09.009
10.1182/blood-2010-06-291633
10.1146/annurev.immunol.24.021605.090727
10.1111/j.0105-2896.2004.00203.x
10.1038/ni.2936
10.4049/jimmunol.1500414
10.1172/JCI31751
10.1182/blood-2011-07-366328
10.1007/s00018-011-0801-8
10.1182/blood-2011-10-384362
10.4049/jimmunol.173.3.1681
10.1073/pnas.1405514111
10.1016/j.immuni.2011.06.003
10.1038/ni.2449
10.1038/ncomms8670
10.1371/journal.pone.0017896
10.1371/journal.pone.0004942
10.1073/pnas.1003457107
10.18632/oncotarget.6107
10.4049/jimmunol.1201507
10.1200/JCO.2008.16.5449
10.4049/jimmunol.0900719
10.1038/ni.3693
10.1016/S0021-9258(18)66732-8
10.1016/j.immuni.2010.08.004
10.4049/jimmunol.165.5.2556
10.1016/j.ceb.2016.02.002
Y. Shimizu, R. DeMars, Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A, -B, -C null human cell line. J. Immunol. 142, 3320–3328 (1989).
10.1038/ni.1749