Abstract
Cell metabolism plays a pivotal role in regulating the effector functions of immune cells. Stimulatory cytokines, such as interleukin (IL)-2 or IL-12 and IL-15, activate glycolysis and oxidative phosphorylation in natural killer (NK) cells to support their enhanced effector functions. IL-10, a pleiotropic cytokine, is known to suppress macrophage activation but stimulate NK cells. However, it remains unclear if IL-10 has an effect on the metabolism of human NK cells and if so, what metabolic mechanisms are affected, and how these metabolic changes are regulated and contribute to the effector functions of NK cells. In this study, we demonstrate that IL-10 upregulates both glycolysis and oxidative phosphorylation in human NK cells, and these metabolic changes are crucial for the enhanced effector functions of NK cells. Mechanistically, we unravel that IL-10 activates the mammalian target of rapamycin complex 1 (mTORC1) to regulate metabolic reprogramming in human NK cells.
Highlights
Natural killer (NK) cells are innate cytotoxic lymphocytes that target tumor and virus-infected cells to prevent malignancy and systemic infection [1, 2]
Our current study showed that IL-10 treatment increases natural killer (NK) cell production of IFN-γ and enhances their cytotoxicity by augmenting their degranulation and FasL expression
We demonstrated that IL-10 boosts glycolysis and oxidative phosphorylation (OXPHOS) of NK cells, and these metabolic changes are required for the enhanced effector functions of IL-10 stimulated NK cells
Summary
Natural killer (NK) cells are innate cytotoxic lymphocytes that target tumor and virus-infected cells to prevent malignancy and systemic infection [1, 2]. The activation of NK cells is regulated by the engagement of NK cell receptors (NKRs) and cytokines [1]. NK cells express both activating (e.g., NKG2D and CD16) and inhibitory (e.g., NKG2A) NKRs, which recognize corresponding ligands on target cells and transduce either stimulatory or inhibitory signals [5]. The overall balance of stimulatory and inhibitory signals determines whether NK cells are activated or inhibited [6]. Cytokines play critical roles in regulating NK cell activation. Stimulatory cytokines, such as interleukin (IL)-2, IL-12 and IL-15, promote proliferation and activation of NK cells [7], while inhibitory cytokines, IL-10 for NK Cell Metabolism e.g., transforming growth factor β (TGF-β), inhibit NK cell maturation, proliferation and functions [8, 9]
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