Final Report Summary - INKT CELLS (Omental iNKT cells as an Immunological Tools in Obesity and Cancer)
Over 1.4 billion adults and 40 million children under age 5 are overweight or obese worldwide, and obesity is a major risk factor for many serious diseases such as cardiovascular disease, diabetes, and cancer. The increasing incidence of obesity and these associated diseases has focused attention on the effectiveness of therapeutic strategies used to treat these disorders. Inflammation is an underlying cause or contributor to many of these diseases, and thus, preventing 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. In particular, we now know that human and murine adipose tissue harbours a distinct collection of immune cells including an accumulation of otherwise scarce lymphocytes. We have identified, for the first time, the enrichment of one such lymphocyte, the invariant natural killer (iNKT) cell in human and murine adipose tissue. The overall aim of this study is to investigate the physiological relevance of iNKT cells in fat and to investigate and design ways to exploit their functions for therapeutic targets in obesity and metabolic disorders. Importantly, we have identified a unique, striking role for iNKT cells in regulating adipose tissue inflammation, metabolism, and weight control.
iNKT cells are innate T cells that are highly conserved in mammals. Unlike adaptive T cells that recognize peptides presented by MHC class molecules, iNKT cells recognize lipid antigens presented by CD1d antigen presenting molecules. Thus, iNKT cells represent the lipid-sensing arm of the immune system. In mice, iNKT cells have been found to protect from autoimmunity and cancer, and to mediate host defences in a variety of models. Until now, their role in metabolism has not been explored. During this Marie Curie Fellowship, we have discovered an early and critical protective role for iNKT cells in the development of obesity and the metabolic syndrome. First, we discovered that iNKT deficient mice (CD1d-/- and Ja18-/- mice) on normal diets were obese and when iNKT deficient mice we placed on a high fat diet (HFD), they gained weight faster and displayed more rapid and severe insulin resistance and type 2 diabetes. Adoptive transfer of iNKT cells into iNKT deficient (Jα18-/- mice and CD1d-/- mice) improved glucose handling. Activation of iNKT cells by α-galactosylceramide (αGalCer) promoted M2 macrophage polarization and resulted in weight loss and improved fatty liver and insulin resistance (Figure 1). Together, these studies have revealed one of the clearest examples of the regulatory function of iNKT cells, indicating that they maintain healthy adipose tissue under normal conditions and correct obesity and metabolic disorder when stimulated under high fat diet conditions. However, we have also shown that in obese humans and mice these iNKT cells are greatly reduced, and therefore their protective effects may be blunted. After starting a HFD, iNKT cell numbers fell in adipose tissue and correlated inversely with macrophage infiltration. Therefore understanding what happens to iNKT cells during obesity, and how to prevent their loss, or how to activate the remaining pool during obesity may provide exciting therapeutic avenue to treat obesity and the metabolic syndrome.
The discovery of an enriched population of regulatory iNKT cells in human and murine adipose tissue, that can positively regulate metabolism, but are depleted in obesity, raises a number questions. These include 1) Are iNKT cells resident in adipose tissue, 2) What is the basis for the unique function of iNKT cells in adipose tissue, 3) Does adipose tissue contain a lipid ligand for iNKT cell survival and activation, 4) What are the main targets of iNKT cell regulation in adipose tissue, 5) Can iNKT cells be targeted with lipid antigens to improve inflammation and restore metabolic health in obesity. In second stage of the Marie Curie Fellowship, we addressed each of these key questions.
Using parabiosis, we show that this novel iNKT cell subset is resident in adipose tissue with almost no recirculation from the circulation, unlike all other lymphocytes in adipose tissue. We identified that adipose iNKT cells have an unusual gene expression profile, including transcription factors unique to adipose iNKT cells that are responsible for their unique function, especially their IL-2 and IL-10 production. Furthermore, through their production of these regulatory cytokines, iNKT cells can control adipose Treg and other T cell survival, proliferation and suppressor function. In addition, adipose iNKT cells themselves can act as suppressor cells, and can induce a phenotypic switch of macrophages through their IL-10 production. Strong evidence shows that human and murine adipose tissue contain lipid antigens recognized by iNKT cells, and work is underway to identify these specific lipids.
Potential Impact and use:
Obesity threatens to shorten the human lifespan by 5-20 years, the biggest burden being obesity-induced diseases, which are increasing at a staggering rate in the western world and this project has clear socio-economic motives. Great interest exists in how to harness iNKT cells because they are capable of producing massive amount of cytokines. This is particularly true in the tissues where they are highly enriched under homeostatic conditions, namely the liver and adipose tissue. The ability to selectively activate adipose iNKT cells provides an entirely new therapeutic direction for treating obesity and type II diabetes. We predict, based on preliminary data, that adipose lipids will induce iNKT cells to produce beneficial cytokines locally, improving inflammation in adipose tissue. Active lipid ligands can be synthesized to clinical grade standards for administration to patients. Lipid antigens that target iNKT cells, as well as other bioactive lipids, have been used clinically to treat patients with cancer, and are the subject of many clinical trials for various cancers and including melanoma and prostate cancer as well as autoimunme diseases (including here in Boston, MA). Several companies already have lipid based drug therapeutics for other purposes (eg. Ono Pharmaceuticals, NKT Therapeutics). Therefore the pharmaceutical path to drug development for metabolic disorder associated with adipose tissue inflammation is fully viable.
iNKT cells are innate T cells that are highly conserved in mammals. Unlike adaptive T cells that recognize peptides presented by MHC class molecules, iNKT cells recognize lipid antigens presented by CD1d antigen presenting molecules. Thus, iNKT cells represent the lipid-sensing arm of the immune system. In mice, iNKT cells have been found to protect from autoimmunity and cancer, and to mediate host defences in a variety of models. Until now, their role in metabolism has not been explored. During this Marie Curie Fellowship, we have discovered an early and critical protective role for iNKT cells in the development of obesity and the metabolic syndrome. First, we discovered that iNKT deficient mice (CD1d-/- and Ja18-/- mice) on normal diets were obese and when iNKT deficient mice we placed on a high fat diet (HFD), they gained weight faster and displayed more rapid and severe insulin resistance and type 2 diabetes. Adoptive transfer of iNKT cells into iNKT deficient (Jα18-/- mice and CD1d-/- mice) improved glucose handling. Activation of iNKT cells by α-galactosylceramide (αGalCer) promoted M2 macrophage polarization and resulted in weight loss and improved fatty liver and insulin resistance (Figure 1). Together, these studies have revealed one of the clearest examples of the regulatory function of iNKT cells, indicating that they maintain healthy adipose tissue under normal conditions and correct obesity and metabolic disorder when stimulated under high fat diet conditions. However, we have also shown that in obese humans and mice these iNKT cells are greatly reduced, and therefore their protective effects may be blunted. After starting a HFD, iNKT cell numbers fell in adipose tissue and correlated inversely with macrophage infiltration. Therefore understanding what happens to iNKT cells during obesity, and how to prevent their loss, or how to activate the remaining pool during obesity may provide exciting therapeutic avenue to treat obesity and the metabolic syndrome.
The discovery of an enriched population of regulatory iNKT cells in human and murine adipose tissue, that can positively regulate metabolism, but are depleted in obesity, raises a number questions. These include 1) Are iNKT cells resident in adipose tissue, 2) What is the basis for the unique function of iNKT cells in adipose tissue, 3) Does adipose tissue contain a lipid ligand for iNKT cell survival and activation, 4) What are the main targets of iNKT cell regulation in adipose tissue, 5) Can iNKT cells be targeted with lipid antigens to improve inflammation and restore metabolic health in obesity. In second stage of the Marie Curie Fellowship, we addressed each of these key questions.
Using parabiosis, we show that this novel iNKT cell subset is resident in adipose tissue with almost no recirculation from the circulation, unlike all other lymphocytes in adipose tissue. We identified that adipose iNKT cells have an unusual gene expression profile, including transcription factors unique to adipose iNKT cells that are responsible for their unique function, especially their IL-2 and IL-10 production. Furthermore, through their production of these regulatory cytokines, iNKT cells can control adipose Treg and other T cell survival, proliferation and suppressor function. In addition, adipose iNKT cells themselves can act as suppressor cells, and can induce a phenotypic switch of macrophages through their IL-10 production. Strong evidence shows that human and murine adipose tissue contain lipid antigens recognized by iNKT cells, and work is underway to identify these specific lipids.
Potential Impact and use:
Obesity threatens to shorten the human lifespan by 5-20 years, the biggest burden being obesity-induced diseases, which are increasing at a staggering rate in the western world and this project has clear socio-economic motives. Great interest exists in how to harness iNKT cells because they are capable of producing massive amount of cytokines. This is particularly true in the tissues where they are highly enriched under homeostatic conditions, namely the liver and adipose tissue. The ability to selectively activate adipose iNKT cells provides an entirely new therapeutic direction for treating obesity and type II diabetes. We predict, based on preliminary data, that adipose lipids will induce iNKT cells to produce beneficial cytokines locally, improving inflammation in adipose tissue. Active lipid ligands can be synthesized to clinical grade standards for administration to patients. Lipid antigens that target iNKT cells, as well as other bioactive lipids, have been used clinically to treat patients with cancer, and are the subject of many clinical trials for various cancers and including melanoma and prostate cancer as well as autoimunme diseases (including here in Boston, MA). Several companies already have lipid based drug therapeutics for other purposes (eg. Ono Pharmaceuticals, NKT Therapeutics). Therefore the pharmaceutical path to drug development for metabolic disorder associated with adipose tissue inflammation is fully viable.