My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) alter immunity. We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity. Leptin is secreted from adipocytes in proportion to adipocyte volume and is therefore decreased in malnutrition and increased in obesity. We have found that leptin is a critical regulator of effector T cell glucose metabolism and thereby drives effector T cell activation. From these initial findings, we have established further lines of investigation, as summarized below.
(1) Determining mechanisms of T cell dysfunction in malnutrition – our goal is to identify mechanisms by which malnutrition and decreased leptin alter T cell function and susceptibility to infection. To that end, we are testing the effect of malnutrition on T cell immunity to Salmonella in a mouse model. We will then determine the role of leptin signaling and glucose metabolism in T cell infection response in this model. Finally, we plan to investigate the effects of malnutrition on epigenetic mechanisms and metabolic signaling pathways that are critical for T cell response.
(2) Identifying molecular mechanisms by which leptin and nutrition target T cell immunity in multiple sclerosis – our goal is to identify mechanisms by which malnutrition and associated hypoleptinemia alter T cell subset differentiation, resulting in T cell dysfunction and decreased susceptibility to experimental autoimmune encephalomyelitis. We have recently been awarded a three-year grant from the National MS Society for these studies.
(3) Mechanisms of T cell inflammation in obesity-induced type 2 diabetes – Our goal is to identify molecular mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes. We hypothesize that obesity-associated hyperleptinemia directly promotes T cell glycolytic metabolism to drive T cell effector fate and inflammation. To test our hypothesis, we will first identify the direct role of leptin in Teff versus Treg differentiation and metabolism and in the development of insulin resistance in obesity. Second, we will examine signaling pathways by which leptin may mediate changes to T cell differentiation and metabolism to promote inflammation and insulin resistance in obesity.
Overall, our work is highly interdisciplinary and involves the fields of immunology, endocrinology, nutrition, and cellular metabolism. We have formed collaborations with several basic scientists throughout Duke University with expertise in T cell biology, cellular metabolism, epigenetics, and signaling. Additionally, through our membership in the Duke Molecular Physiology Institute and the Sarah W. Stedman Nutrition and Metabolism Center at Duke, we have access to cutting-edge, high-resolution metabolomic tools to assist in our investigations.