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

描述（由申请人提供）：强大的T细胞介导的免疫反应是保护免受感染和某些癌症的关键组成部分。新出现的证据表明，除了增加心血管疾病和癌症的发病率外，肥胖还损害了感染风险和严重程度增加的小鼠的T细胞依赖免疫监视机制。人们认识到，T细胞的胸腺输出建立了人类幼稚T细胞库的大小和多样性。有趣的是，到了中年，胸腺经历了一个退化过程，其特征是幼稚T细胞产生减少，胸腺空间被脂肪细胞取代。众所周知，饮食性肥胖会增加一些异位部位（如肌肉、肝脏）的脂质沉积，并损害器官功能。同样，我们已经证明，小鼠的肥胖加剧了促进胸腺异位脂质脂肪细胞沉积的机制，并减少了胸腺幼稚T细胞的产生。基于肥胖限制T细胞受体（TCR）多样性的小鼠模型数据和肥胖人群的初步发现，我们提出验证肥胖加速免疫衰老和过度减肥可以挽救人类胸腺功能丧失和T细胞多样性和功能限制的假设。该项目的总体目标是评估肥胖与免疫系统之间关系的具体假设和预测，特别是胸腺增生和T细胞介导的免疫，这对理解减肥可能增强人类免疫监测的机制具有重要意义。因此，我们建议通过减肥手术和热量限制来研究肥胖和随后的减肥对人类胸腺功能含量、胸腺生成、T细胞功能和TCR多样性的影响。我们提出了三个具体目的：1)验证肥胖增加胸腺异位脂肪细胞发育的预测。2)验证肥胖降低胸腺生成和损害T细胞功能的预测。3)验证肥胖引起的功能性胸腺空间、胸腺功能和异常免疫功能的减少可以通过减肥治疗来挽救的预测。

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. PUBLIC HEALTH RELEVANCE: Obesity is associated with increased risk and severity of infections and cancers. T cell mediated immune- surveillance is vital for protection against pathogens as well as certain cancers. To date, no studies in humans have evaluated whether obesity impacts the protective T cell immune function. The overall goal of this project is to determine the mechanism of immune dysfunction in obesity and investigate the impact of distinct weight loss treatments on reversing the decline in immunity.