About our research interests
My lab is interested in understanding the cross-talk between the innate immune system and the metabolic system, and the key molecules involved. A major focus is to understand the cellular metabolic decisions controlling the effector fate of leukocytes that may ultimately open doors to manipulate the immune system in metabolic disorders.
This also extends to other situations of altered metabolism, such as in the tumor microenvironment. The goal is to integrate the two aspects of immunometabolism (systemic and intrinsic bioenergetics) to enable us to find metabolic targets for immune cell modulation and ultimately manipulate them in human disease.
1. Innate immune cells in adipose tissue
The immune system in adipose tissue is largely under-appreciated, yet adipose tissue contains an incredibly unique and substantial immune system. Adipose tissue covers much of the body, and can account for 50% of body mass in obesity. Each adipose depot in humans and mice has its own substantial immune system with collectively more lymphocytes than the liver. More surprising is that adipose lymphocytes have unique subsets and functions compared to their counterparts elsewhere in the body. A major component of the adipose immune system is non-MHC restricted ‘unconventional’ T cells which are often less diverse cells including iNKT cells, gd T cells, MAIT cells. We work on understanding the physiological basis for this enrichment of innate and ‘unconventional’ lymphocytes in humans and mice. Our goal is to understand this aspect of immunity, what regulates it, and the full potential it holds.
2. Adipose iNKT cells and adipose antigens
iNKT cells are the innate lipid-sensing arm of the immune system. Since our discovery that mammalian adipose tissue is enriched for iNKT cells, we have identified a critical role for iNKT cells in regulating adipose inflammation and body weight. Using a multi-disciplinary approach, we aim to identify key signals and molecules used by iNKT cells to induce metabolic control and weight loss in obesity. As iNKT cells have an invariant T cell receptor (TCR), they likely recognize one particular antigen or a small pool of antigens. iNKT cells are also highly conserved throughout species, as is their lipid-presenting CD1d molecules, suggesting this is an extremely important aspect of immunity, but the basis for this conservation is still not fully understood. Yet, non-polymorphic CD1d molecules and clonal lipid-reactive iNKT cells are highly enriched in adipose tissue throughout the body, and are regulatory in nature. Thus, in this instance, iNKT cells and the CD1d lipid presentation system may not be primarily designed to protect us from pathogens but rather, to regulate metabolic or lipid processes occurring in adipose tissue. Elucidating why regulatory iNKT cells are enriched in fat is key to understanding why this aspect of immunity in fat has been conserved.
3. Obesity, immunity and cancer
At least 2.8 million people die each year as a result of being overweight or obese, the biggest burden being obesity-related diseases. In addition to type 2 diabetes and cardiovascular disease, obesity is associated with an increased risk of cancer and infections, suggesting the immune system is compromised. A striking 40% of certain cancers are attributed to obesity, and it is expected that obesity will soon replace smoking as the leading preventable cause of cancer. Potential mechanisms for the increased risk of obesity-induced cancer include overproduction of hormones (eg. oestrogens), adipokines (eg. leptin) and insulin, which directly promote tumour growth and proliferation. Less is known about the impact of obesity-induced immune dysregulation on cancer risk. Our work focuses on investigating the effects of obesity on innate immune surveillance, which may be responsible for the increased cancer and infection risks in obesity. We focus on natural killer (NK) cells, which are the body’s first defense against infections and cancer.