Nutritional immunology: function of natural killer cells and their modulation by resveratrol for cancer prevention and treatment

Abstract

Natural killer (NK) cells as part of the innate immune system represent the first line of defence against (virus-) infected and malignantly transformed cells. The emerging field of nutritional immunology focuses on compounds featuring immune-modulating activities in particular on NK cells, which e.g. can be exploited for cancer prevention and treatment. The plant-based nutrition resveratrol is a ternary hydroxylated stilbene, which is present in many foods and beverages, respectively. In humans it comprises a large variety of distinct biological activities. Interestingly, resveratrol strongly modulates the immune response including the activity of NK cells. This review will give an overview on NK cell functions and summarize the resveratrol-mediated modulation thereof.

Keywords: Immune modulation; Innate immune system; NK cell activity; Nutritional immunology; Resveratrol.

Fig. 1

NK cells execute multiple tasks in innate immunity, they are i) responsible for direct defence of the host organism by checking for and eliminating stressed or transformed autologous cells with low MHC I levels, ii) execute ADCC in case of virus infected cells by binding IgG to FcγRIII (CD16) receptor, or iii) eliminate microbes by recognition of conserved structures with different PRRs. On the other side NK cells influence maturation and activation of other immune cells and e.g. can kill immature DCs or M0 and M2 macrophages and thus selectively let activated APCs present antigens to T cells in a controlled manner. Activated T cells can also be killed by NK cell-mediated lysis. NK cells therefore directly manipulate the adaptive immune response by influencing antigen presentation and quantity of other immune cells. Immune cross talk often implies bidirectional activation, which leads, like activating signalling in direct host defence, to enhanced proliferation, cytokine production, and cytotoxicity by increased expression of granzymes, perforin, and granulysin. Numerous cytokines can so be released by NK cells, primarily IFN-γ, TNF-α, and GM-CSF, but also many ILs and various inflammatory chemokines, which attract and traffic e.g. T cells, DCs, monocytes, eosinophils, basophils, or neutrophils. ADCC, antibody-dependent cell-mediated cytotoxicity; CCL, C-C motif ligand; CTL, cytotoxic T lymphocyte; CXCL, C-X-C motif ligand; DNAM-1, DNAX accessory molecule-1; FASL, fragment apoptosis stimulating ligand; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MHC I, major histocompatibility complex I; MIP1, macrophage inflammatory protein 1; NK cells, natural killer cells; NKG2D, natural-killer group 2, member D; NKp30/46, natural killer cell p30/46-related protein; NLR, nucleotide oligomerization domain (NOD)-like receptor; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; RLR, RNA helicase retinoic inducible gene I (RIG-I)-like receptor; TCR, T cell receptor; TLR, Toll-like receptor; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; XCL, X-C motif ligand

Fig. 2

The parent compound of resveratrol is a trihydroxylated stilbene (a). Resveratrol exists in two isomeric forms, cis and trans (b). Its natural occurring glycosidic form is piceid (c) with a glucose molecule linked via a 3-O-β-D-glycosidic bond to cis- or trans-resveratrol

Fig. 3

Resveratrol modulates the NKG2D receptor/NKG2D-L system by increasing expression in NK cells and in transformed target cells. Enhanced expression of NKG2D receptor and cytotoxins in NK cells together with upregulation of NKG2D ligands and DRs on target cell surface lead to enhanced killing efficacy. NK cells use two different mechanisms to kill the targets: i) by cytotoxic granule exocytosis ii) by induction of death receptor-mediated apoptosis. Increased IFN-γ production by resveratrol enhances TRAIL expression, which can facilitate apoptosis induction. Inhibitory signalling is often too weak to prevent NK cell killing due to downregulated expression of MHC I proteins in virus-infected or malignantly transformed cells. Further activating signals can provide NCR ligands of different origin. DR4/5, death receptor 4/5; MHC I, major histocompatibility complex I; MICA/B, MHC class I-related chain A/B; NK cells, natural killer cells; NKG2D, natural-killer group 2, member D; NKp30/44, natural killer cell p30/44-related protein; TRAIL, TNF-related apoptosis-inducing ligand; ULBP1-3, UL16 binding protein 1–3