Impact of Obesity and Weight-Loss Interventions on Immune-Surveillance Mechanisms

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DESCRIPTION (provided by applicant): Robust T cell mediated immune responses are key components of protection from infection and certain cancers. Emerging evidence suggests that, apart from increased incidence of cardiovascular diseases and cancers, obesity also compromises T cell dependent immune-surveillance mechanisms in mice with increased risk and severity of infections. It is recognized that thymic export of T cells establishes the size and diversity of human naive T cell repertoire. Intriguingly, by middle age, thymus undergoes a process of involution characterized by reduced naive T cell production together with replacement of thymic space with adipocytes. Dietary-obesity is known to increase lipid deposition in several ectopic sites such as muscle, liver and compromise organ function. Similarly, we have shown that obesity in mice exacerbates the mechanisms that promote deposition of ectopic lipid-bearing adipocyte in thymus and reduces generation of naive T cells from thymus. Based on our data from mouse models that obesity restricts T cell receptor (TCR) repertoire diversity and preliminary findings in obese humans, we propose to test the hypothesis that, obesity accelerates immunosenescence and excess weight-loss can rescue loss of thymopoiesis and restriction of T cell repertoire diversity and function in humans. The overall goal of this project is to assess specific hypotheses and predictions about the relationship between obesity and immune system - in particular, thymopoiesis and T cell-mediated immunity - with implications for understanding the mechanisms whereby weight-loss might enhance immune- surveillance in humans. Therefore, we propose to study the impact of obesity and subsequent weight-loss through bariatric surgery and caloric restriction on functional thymic content, thymopoiesis, T cell function and TCR diversity in humans. We propose three specific aims, 1) To test the prediction that obesity increases ectopic adipocyte development in thymus. 2) To test the prediction that obesity lowers thymopoiesis and compromises T cell function. 3) To test the prediction that obesity-induced reduction in functional thymic space, thymopoiesis, and aberrant immune function can be rescued by weight-loss therapy.