Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

Abstract

Obesity is associated with an increased risk for several cancer types and an altered phenotype and functionality of natural killer (NK) cells. This study aimed to investigate the association of overweight and obesity with NK cell functions and receptor expression profiles in humans. Therefore, peripheral blood mononuclear cells were isolated from normal weight, overweight, and obese healthy blood donors. In depth analysis of immune cell populations and 23 different surface markers, including NK cell receptors, NK-cell-related markers as well as functional intracellular markers on total NK cells and NK subgroups were performed by multicolor flow cytometry. The data revealed a decreased expression of the activating NK cell receptors KIR2DS4 and NKp46 as well as an increased expression of the inhibitory NK cell receptors NKG2A and Siglec-7 in overweight and obese compared to normal weight individuals. Additionally, the expression of the adhesion molecule CD62L and the maturation and differentiation marker CD27 was downregulated in NK cells of overweight and obese subjects. Furthermore, the cytotoxicity of NK cells against colorectal cancer cells was decreased in overweight and obese subjects. Investigations on underlying killing mechanisms demonstrated a reduced TRAIL expression on NK cells of obese subjects suggesting an impaired death receptor pathway in obesity. The present study gives new insights into an impaired functionality and phenotype of NK cells and NK cell subsets in overweight and obesity. These phenotypic alterations and dysfunction of NK cells might be an explanation for the increased cancer risk in obesity.

High-Fat Diet and Feeding Regime Impairs Number, Phenotype, and Cytotoxicity of Natural Killer Cells in C57BL/6 Mice

“…Until now, only few data exist about the influence of obesity on underlying mechanisms of NK cells. Interestingly, recent studies on human NK cells indicate that the reduced cytotoxicity of NK cells in obese healthy blood donors is induced by an impaired death cell receptor-dependent killing pathway of NK cells (70). Future investigations, like in vivo killing experiments and detailed analyses of killing pathways are necessary to specify underlying mechanisms leading to the decreased NK cell cytotoxicity in obese mice and humans.…”

Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging

“…Studies demonstrated that the expression level of the functional marker TRAIL and the activating NK receptor NKp46 are reduced in obese people [ 63 , 64 , 65 ]. In contrast, studies showed a highly activated NK cells in obese people with increased expression levels of CD69, and programmed cell death protein (PD)-1, as well as the inhibitory receptors of NKB1, CD158b, CD158i, NKG2A/CD94 complex, and Siglec-7 [ 60 , 61 , 63 , 65 ]. In addition, the expressions of CD16, and the adhesion molecule CD62L, and the maturation and differentiation marker CD27 on NK cells are downregulated in obese people [ 63 ].…”

“…In contrast, studies showed a highly activated NK cells in obese people with increased expression levels of CD69, and programmed cell death protein (PD)-1, as well as the inhibitory receptors of NKB1, CD158b, CD158i, NKG2A/CD94 complex, and Siglec-7 [ 60 , 61 , 63 , 65 ]. In addition, the expressions of CD16, and the adhesion molecule CD62L, and the maturation and differentiation marker CD27 on NK cells are downregulated in obese people [ 63 ]. Despite the enhanced activation, NK cells showed a decreased expression level of degranulating marker CD107a and decreased secretion of granzym B and perforin as well as the macrophage inflammatory protein (MIP)-1β in response to cancer cell lines in obese people [ 61 , 64 , 65 ].…”

“…Despite the enhanced activation, NK cells showed a decreased expression level of degranulating marker CD107a and decreased secretion of granzym B and perforin as well as the macrophage inflammatory protein (MIP)-1β in response to cancer cell lines in obese people [ 61 , 64 , 65 ]. Furthermore, the cytotoxicity of NK cells against cancer cells is significantly impaired in obese humans [ 61 , 63 ]. Aside from the characterization of total NK cells, the impact of obesity on the CD56 dim and CD56 bright subset-specific NK cell phenotype has recently been investigated, which demonstrated decreases in NKG2D-positive and CD69-positive CD56 dim NK cells, while there was an increase in NKG2D-positive CD56 bright NK cells in obese people.…”

“…These alterations are correlated with BMI [ 62 ]. Therefore, obesity is associated with alterations of NK cell frequency and phenotypes and an impaired capacity to defend against cancer cells and virus-infected cells [ 61 , 63 ], which contribute to a higher cancer risk and susceptibility to viral infections in obese people. However, weight loss was found to reverse the obesity-induced defects in NK cells [ 62 , 96 , 97 ].…”