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，除了心血管疾病和癌症的发病率增加外，肥胖还损害了感染风险和严重程度增加的小鼠的T细胞依赖的免疫监视机制。T细胞的胸腺输出决定了人类原始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，特征是幼稚T细胞产生减少，胸腺间隙被脂肪细胞取代。众所周知，饮食肥胖会增加肌肉、肝脏等异位部位的脂肪沉积，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含脂脂肪细胞沉积的机制，并减少了胸腺原始T细胞的生成。基于我们的小鼠模型中肥胖限制T细胞受体(TCR)谱多样性的数据和肥胖人类的初步发现，我们建议验证这样的假设：肥胖加速免疫衰老，过度减肥可以挽救人类胸腺生成的丧失和T细胞谱多样性和功能的限制。这个项目的总体目标是评估关于肥胖和免疫系统--特别是胸腺生成和T细胞介导的免疫--之间关系的具体假设和预测，以帮助理解减肥可能增强人类免疫监视的机制。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体重减轻对人类胸腺功能、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标：1)检验肥胖增加胸腺异位脂肪细胞发育的预测。2)检验肥胖会降低胸腺生成并损害T细胞功能的预测。3)验证肥胖所致的功能性胸腺空间减少、胸腺生成和免疫功能异常可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.