IL-15.IL-15Rα complex shedding following trans-presentation is essential for the survival of IL-15 responding NK and T cells

Interleukin (IL)-15 and its specific receptor chain, IL-15R alpha, support the development of various effector cells, including NK and CD8 T cells via a mechanism called trans-presentation. Whereas the dynamic of trans-presentation has been shown to involve the recycling of IL-15R alpha by presenting cells, the way responding cells integrate, or take advantage of this process has not been evaluated yet. To address this question, we set up a trans-presentation model using a membrane-bound IL-15.IL-15R alpha fusion protein, and found that IL-15 is detectable within responding cells following IL-15 trans-presentation. The role of the proteolytic cleavage of IL-15Ra in this process was investigated by generating an uncleavable form of IL-15R alpha. We showed that IL-15 entry into responding cells necessitates the cleavage of IL-15. IL-15R alpha complex from the surface of IL-15 presenting cells, and observed that IL-15R alpha cleavage is associated with a decrease of the duration of Stat5 signaling. Once separated from presenting cells, responding cells are able to recycle IL-15. IL-15R alpha complexes via intracellular compartments, for residual proliferation in a time-limited manner. These studies define an unprecedented cytokine pathway in which the IL-15. IL-15R alpha complex cleaved from presenting cells allows responding cells to internalize, store and use IL-15. IL-15R alpha complex for their own proliferation and survival.