IL-15-PI3K-AKT-mTOR: A Critical Pathway in the Life Journey of Natural Killer Cells

Abstract

Among numerous cytokines modulating natural killer (NK) cell function, interleukin 15 (IL-15) exerts a broad range of effect from development and homeostasis, to activation of mature NK cells during infection. Its significance is further highlighted by clinical trials in which IL-15 is being used to boost the proliferation and anti-tumor response of NK cells. Among the signal transduction pathways triggered by the engagement of IL-15 receptor with its ligand, the PI3K-AKT-mTOR pathway seems to be critical for the IL-15-mediated activation of NK cells, therefore being responsible for efficient anti-viral and anti-tumor responses. This review provides an overview of the role of IL-15 at multiple stages of NK cell life journey. Understanding the pathway by which IL-15 conveys critical signals for the generation of NK cells with efficient effector functions, in combination with established protocols for NK cell expansion ex vivo, will undoubtedly open new avenues for therapeutic applications for immunomodulation against infections and cancers.

Keywords: AKT; IL-15; PI3K; effector functions; mTOR; natural killer cells; proliferation; virus infection.

Figure 1

IL-15 response during natural killer cell development. The developmental stages of mouse NK cells in the bone marrow and periphery are shown, together with the IL-15R expression and IL-15 response. HSC, hematopoietic stem cell; CLP, common lymphoid progenitor; NKP, NK precursor; iNK, immature NK cell; mNK, mature NK cell.

Figure 2

Natural killer cell proliferation during murine cytomegalovirus infection. During MCMV infection, two stages of NK cell proliferation showing pathogen non-specific and specific responses have been proposed. IL-15 drives NK cell proliferation during the early phase of MCMV infection. Upon recognition of CpG motifs from MCMV viral DNA by TLR9, plasmacytoid dendritic cells (pDCs) secrete type I interferons (IFNα/β) and interleukin-12 (IL-12) cytokines. DC-derived IL-12 stimulates NK cells to produce IFN-γ. IFNα/β is transiently produced and reaches a peak level at day 1.5 post-infection and the production is important to induce the expression of IL-15. IL-15 is trans-presented by DCs to NK cells to induce proliferation and enhanced effector functions of NK cells. Activated NK cells can induce perforin/granzyme-mediated apoptosis of MCMV-infected cells by recognizing the viral m157 protein on the cell surface. This direct recognition depends on the activating receptor Ly49H. Proliferation at this stage is dependent on the PI3K–AKT–mTOR pathway. The interaction between Ly49H and the MCMV-encoded protein m157 drives the proliferation and expansion of Ly49H⁺ NK cells on days 6–7 post infection. Notably, this proliferation can occur in IL-15- and IL-15Rα-deficient mice during MCMV infection and is independent of the PI3K–AKT–mTOR pathway.