Natural Killer Cells Display an Activated Phenotype but Reduced Effector Functions in Obese Patients

Abstract

The impact of adiposity on the immune system remains largely unexplored. While obesity has been suggested to be a predisposing or adverse prognostic factor in certain neoplastic diseases it is not yet clear to what extent this may involve the innate or adaptative immune systems. Adipose tissue produces a large number of secreted molecules, or adipocytokines, which may have immunomodulatory functions. This project aimed to determine whether phenotypical and/or functional properties of circulating natural killer (NK) cells were influenced by body mass index (BMI). In a preliminary study, 47 patients with no history of hematological malignancy were included, including 14 healthy volunteers with a normal BMI (18.5-25), 10 patients considered to be overweight (25 < BMI < 30), 11 patients considered as obese (BMI > 30) and 12 patients who were previously obese and had lost weight. Peripheral blood was analyzed by flow cytometry for the following markers: activating receptors (CD16, C161, DNAM-1, 2B4, NKG2C, NKG2D, NKp46, NKp30), inhibitor receptors (NKG2A, KIR2DL1, KIR2DL2, KIR3DL1), activation markers (CD69, granzyme B, NKG2C), maturation markers (CD56, CD57, CD94, CX3CR1) and cytotoxicity markers (perforin, NKG7). Moreover the capacity of NK cells to degranulate and to produce several cytokines (TNF, IFN-g) or chemokines (MIP1-b) in response to stimulation by K562 cells or Rituximab coated -tumor B cells was evaluated.Results showed a positive correlation between BMI and total number of circulating NK cells, with a significant difference between lean patients and obese patients. Immunophenotypic analyses showed that NKp46 and CD94 expression (measured by Mean Fluorescence Intensity) were both significantly reduced with increased BMI. NK cells from obese patients also show signs of activation, characterized by an elevation of the expression of CD69 and granzyme B and a reduction of the expression of CD16. The ability of NK cells to be activated in the presence of cell lines was also reduced in obese patients: NK cell secretion of IFN-g and MIP-1b in the presence of Granta cells or MIP-1b in the presence of K562 decreased linearly with increasing BMI. NK cell degranulation upon co-culture with K562 cells was also negatively correlated with BMI. In these different assays pre-obese and ex-obese patients scored intermediate between lean and obese patients. Overall these results suggest in vivo activation and exhaustion of NK cells in obese patients. These cells are thus potentially less likely to participate as effector cells in immunotherapeutic regimens. DisclosuresNo relevant conflicts of interest to declare.