Dysregulation of Natural Killer Cells in Obesity

Abstract

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.

Keywords: NK cell; adipose tissue; cancer; metabolism; obesity.

Figure 1

Overview of NK cell phenotype in health and obesity (A) schematic detailing human NK cell phenotype; surface molecules (CD56, CD16, natural killer group (NKG)2 family and killer-cell immunoglobulin-like receptors (KIRs), cytokine receptors (Interleukin(IL)-2, IL-12, IL-15 and IL-18) and effector molecules (cytokine and lytic molecule) production; (B) schematic detailing the impact of obesity on NK cells (lower cell frequencies, reduced cytokine production and reduced cytotoxicity); (C) schematic detailing the impact of weight loss on NK cells (restored frequencies, effector molecule production and cytotoxicity).

Figure 2

Overview of obesity induced changes in NK cell metabolism and function (A) in healthy individuals upon activation, NK cells increase their glycolytic metabolism mediated by mammalian target of rapamycin (mTOR), resulting in interferon (IFN)-γ production and tumor cell lysis; (B) in obese individuals, NK cells increase their expression of lipid uptake receptors (CD36, LDLR) resulting in increased uptake of free fatty acids. Upon activation, NK cells fail to activate mTOR and glycolytic metabolism resulting in decreased IFN-γ production, altered polarization of degranulation and defective tumor cell lysis.