Trans-Endocytosis Of Intact Il-15r Alpha-Il-15 Complex From Presenting Cells Into Nk Cells Favors Signaling For Proliferation

Interleukin 15 (IL-15) is an essential cytokine for the survival and proliferation of natural killer (NK) cells. IL-15 activates signaling by the beta and common gamma(gamma(c)) chain heterodimer of the IL-2 receptor through trans-presentation by cells expressing IL-15 bound to the alpha chain of the IL-15 receptor (IL-15R alpha). We show here that membrane-associated IL-15R alpha-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 surfacebound IL-15R alpha-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 alpha-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 StatS phosphorylation. Thus, trans-endocytosis of membrane-associated IL-15R alpha-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.