Abstract
Natural killer (NK) cells were so named for their uniqueness in killing certain tumor and virus-infected cells without prior sensitization. Their functions are modulated in vivo by several soluble immune mediators; interleukin-15 (IL-15) being the most potent among them in enabling NK cell homeostasis, maturation, and activation. During microbial infections, NK cells stimulated with IL-15 display enhanced cytokine responses. This priming effect has previously been shown with respect to increased IFN-γ production in NK cells upon IL-12 and IL-15/IL-2 co-stimulation. In this study, we explored if this effect of IL-15 priming can be extended to various other cytokines and observed enhanced NK cell responses to stimulation with IL-4, IL-21, IFN-α, and IL-2 in addition to IL-12. Notably, we also observed elevated IFN-γ production in primed NK cells upon stimulation through the Ly49H activation receptor. Currently, the fundamental processes required for priming and whether these signaling pathways work collaboratively or independently for NK cell functions are poorly understood. To identify the key signaling events for NK cell priming, we examined IL-15 effects on NK cells in which the pathways emanating from IL-15 receptor activation were blocked with specific inhibitors. Our results demonstrate that the PI3K–AKT–mTOR pathway is critical for cytokine responses in IL-15 primed NK cells. Furthermore, this pathway is also implicated in a broad range of IL-15-induced NK cell effector functions such as proliferation and cytotoxicity. Likewise, NK cells from mice treated with rapamycin to block the mTOR pathway displayed defects in proliferation, and IFN-γ and granzyme B productions resulting in elevated viral burdens upon murine cytomegalovirus infection. Taken together, our data demonstrate the requirement of PI3K–mTOR pathway for enhanced NK cell functions by IL-15, thereby coupling the metabolic sensor mTOR to NK cell anti-viral responses.
Highlights
Natural killer cells are innate immune lymphocytes that were so named for their propensity to kill target cells without the need for antigenic stimulation [1]
Because the priming effect has only been shown with respect to enhanced responsiveness to IL12 when co-stimulated with IL-2 or IL-15 [8, 21, 22, 28,29,30], we hypothesized that IL-15 “priming” of Natural killer (NK) cell responses can be extended to a broader range of cytokines that transmit their signal by employing the JAK–signal transduction and activation of transcription (STAT) pathway
Our data indicate that NK cells pre-stimulated with IL-15 display enhanced phosphorylation of STAT4 and increased IFN-γ production upon IL-12 stimulation compared to naïve cells (Figures 1A,B)
Summary
Natural killer cells are innate immune lymphocytes that were so named for their propensity to kill target cells without the need for antigenic stimulation [1]. They are equipped with several inhibitory receptors that bind to certain surface molecules like selfmajor histocompatibility complex (MHC) class I thereby avoiding destruction of healthy cells. Signals through activating receptors stimulate NK cells to release preexisting cytotoxic granules such as perforin and granzymes thereby destroying infected and cancerous cells. Unlike human NK cells, naïve mouse NK cells are devoid of perforin and granzyme B cytotoxic granules and require additional stimulations to induce rapid translation of their pre-existing mRNAs in order to be fully equipped for action [9]
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