Convergence of Systemic and Cellular Immunometabolism

Figure: Example of systemic and intrinsic immunometabolic convergence

Lean adipose tissue is characterized by an enrichment of anti-inflammatory immune cells whose phenotype is driven by metabolic changes induced by the adipose microenvironment. Adipose tissue lipids bind to PPARg in regulatory T cells and alternatively activated (anti-inflammatory) macrophages and promote a regulatory program associated with oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Overfeeding and obesity induce multiple changes in the adipose microenvironment that can alter the metabolic program of adipose-resident immune cells and promote inflammation. Reduced oxygen levels can induce HIF-1a expression and a glycolytic program, which can shift the balance away from regulatory T cells and toward pathogenic Th17 cells. Free fatty acids from ruptured adipocytes can induce pro-inflammatory macrophage polarization through TLR signaling. Additionally, signaling from proinflammatory cytokines such as TNF and IFNγ can shift macrophage metabolism toward glycolysis, which further promotes their pro-inflammatory properties. The net effect of this pro-inflammatory response to obesity induces insulin resistance locally and systemically.

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.

Figure: Immunometabolic homeostasis during steady state and obese conditions
In lean adipose tissue, immune cells and neighboring adipocytes interact to regulate adipocyte lipid handling and insulin sensitivity, and prevent inflammation. IL-10 production by iNKT, Tregs and M2 macrophages and IL-4 production by eosinophils are important for this homeostasis. During adipose expansion in obesity, there is a loss of iNKT cells and Tregs, and a phenotypic switch in macrophages from M2 to M1, accumulating around hypertrophic rupturing adipocytes.

Adipose iNKT cells

Obesity has reached epidemic proportions globally. At least 2.8 million people die each year as a result of being overweight or obese, the biggest burden being obesity-related diseases. It is now clear that inflammation, particularly in adipose tissue itself, interferes with insulin signaling and is an underlying cause or contributor to many of these diseases, including type 2 diabetes, atherosclerosis, and cancer. Recognition that the immune system can regulate metabolic pathways has prompted a new way of thinking about diabetes and weight management. Despite much recent progress, most immunometabolic pathways, and how to target them, are currently unknown. One such pathway is the cross-talk between invariant natural killer (iNKT) cells and neighboring adipocytes. 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. Adipose iNKT cells are unusual regulatory iNKT cells which we have shown, using parabiosis, are resident in adipose tissue. We study adipose iNKT cells to identify key signals and molecules used by iNKT cells to induce metabolic control and weight loss in obesity. We are also investigating potential lipid antigens in adipose tissue which may activate iNKT cells. This will perhaps explain iNKT cell conservation in adipose depots, and provide safe tools for iNKT cell manipulation in vivo.

Lynch, Immunology, Review 2014

γδ T cells

The lab studies γδ T cells in humans and mice, and the transcriptional programs that control the individual γδ T cell subsets. It may be beneficial to understand what governs their cytokine production, namely IFNg and IL-17 at time of inflammation, such as in the skin, or in tumors.

Figure : Heat map of γδ T cell subsets in humans

NK Cells

One key aspect of our research is to understand the effects of obesity on immune surveillance, and the effects of the immune system on obesity. The global obesity epidemic and the realization that chronic, low-grade inflammation is a characteristic feature of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease triggered a massive surge in studying whole-body metabolism. However, in addition to metabolic disease, obesity is associated with an increased risk of cancer and infections A striking 49% of certain cancers are attributed to obesity, and it is expected that obesity will soon replace smoking as the leading preventable cause of cancer. It has been proposed that increased levels of insulin, hormones, and adipokines are responsible for the increased cancer risk due to their direct effect on tumour growth and proliferation. However we believe that obesity also impacts normal 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. Defects in NK cells can lead to fatal infections and increased development of cancer.