A Brief IL-15 Pulse Results in JAK3-Dependent Phosphorylation of ITAM-Associated Signaling Molecules and a Long-Lasting Priming Imprint in Mouse NK Cells

Abstract

Interleukin-15 (IL-15) is responsible for natural killer (NK) cell priming but the dynamics, kinetics and molecular mechanisms of NK cell priming are not well characterised. We here show that as little as 5 minutes of IL-15 treatment of NK cells followed by removal of excess cytokine, left a long-lasting but reversible priming imprint characterised by enhanced calcium flux, degranulation and INF-gamma production after activation of the ITAM-encoded receptor NK1.1. Enhanced function was linked to ROS production and to an increased steady-state phosphorylation of signalling molecules downstream of ITAM-containing activating receptors, including LCK and SLP-76. A crosstalk between the IL-15 receptor and activating receptors in NK cells was suggested by a dampening effect of IL-15-dependent priming by JAK3 inhibition. Increased STAT5 phosphorylation and calcium flux responses remained for at least three hours after IL-15 removal but then disappeared. Our study extends the understanding of NK cell priming and is relevant to fundamental and applied questions in NK cell biology.