INKT CELLS

Omental iNKT cells as an Immunological Tools in Obesity and Cancer

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 Obiettivo del progetto (Objective)

'Invariant natural killer T (iNKT) cells play crucial roles in protection against cancer in murine models. We have described large populations of iNKT cells in the human omentum, which until now were thought to be rare in humans. Omental iNKT cells display potent cytotoxicity against autologous tumors in vitro however, in patients with obesity and cancer, iNKT cells are depleted. This fellowship seeks to answer many questions which have remained elusive since the discovery of iNKT cells 15 years ago, such as what is their physiological role in humans, why do they accumulate in fat, and what is the natural lipid ligand for these cells. We will study omental iNKT cells and omental lipids in human and murine fat and investigate their role in obesity and cancer using in vivo and in vitro techniques, interventional studies and genetically defined specific gene-deleted animals. In addition, I hypothesise a completely novel function for iNKT cells in the prevention of obesity related chronic inflammation and metabolic disorders. Our research may lead to the discovery of novel immunotherapeutics for the treatment of malignancy and certain obesity-related complications.'

Introduzione (Teaser)

Obesity is a major risk factor for many serious diseases such as cardiovascular disease, diabetes, and cancer. The increasing incidence of obesity focuses attention on the need for mitigating obesity.

Descrizione progetto (Article)

Inflammation is a major contributor to many of these diseases and prevention of obesity-induced inflammation should be a key priority in tackling the obesity burden. Immunological alterations caused by obesity are pivotal mediators in the chronic inflammation that drives obesity-induced metabolic disorder.

iNKT cells are innate T cells of the immune system that are highly conserved in mammals. Unlike adaptive T cells that recognise peptides, iNKT cells recognise lipid antigens. The EU-funded 'Omental iNKT cells as an immunological tools in obesity and cancer' (INKT CELLS) project aimed to investigate the role of iNKT cells in fat tissue and devise novel therapeutic strategies.

Researchers found that iNKT-deficient mice on a normal diet were obese. On a high fat diet they gained weight faster and displayed rapid and severe insulin resistance and type 2 diabetes. Adoptive transfer of iNKT cells into iNKT-deficient mice improved glucose metabolism. These studies demonstrated that iNKT cells maintain healthy adipose tissue under normal conditions and correct obesity under high fat diet conditions. However, in obese humans and mice these iNKT cells are greatly reduced, and therefore their protective effects may be lost.

Using parabiotic experiments, researchers showed that this iNKT cell subset is resident in adipose tissue. Expression profile of these cells included transcription factors that are responsible for their unique function, especially interleukin (IL)-2 and IL-10 production. Through production of these cytokines, iNKT cells control adipose Treg and other T cell survival, proliferation and suppressor functions.

Researchers obtained strong evidence that human and murine adipose tissues contain lipid antigens recognised by iNKT cells. Currently investigation is underway to identify these specific lipids.

Obesity and obesity-associated diseases are increasing at a staggering rate in the western world and this project has clear socio-economic impact. The ability to selectively activate adipose iNKT cells provides an entirely new therapeutic direction for treating obesity and type II diabetes.