Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

脂肪组织包含一个由白细胞组成的网络，这些细胞通过产生促炎信号来应对肥胖，这些信号有助于新陈代谢疾病。与此同时，有强有力的证据表明，肥胖会损害许多健康的免疫反应，并导致包括呼吸道病毒在内的许多疾病的病情加重。我们目前还不清楚这种二分法背后的机制。解决这一差距可以揭示抑制过度活跃的免疫系统以改善胰岛素抵抗的机制，还可以确定保存正常免疫反应以改善肥胖者健康的机制。这项提议试图通过关注脂肪组织免疫系统的先天和适应性组件在老鼠和人类中相互作用的机制来了解脂肪组织的免疫反应。我们的中心假设是，肥胖产生的慢性促炎环境会触发T细胞和髓系衰竭。我们进一步假设，脂肪组织巨噬细胞(ATM)和树突状细胞(ATDC)的多样性形成了脂肪组织T细胞反应，从而损害了脂肪组织炎症的健康化解。这一假设的前提是基于上一轮赠款周期中发表的工作，以及初步数据显示，肥胖人类和小鼠肥胖脂肪组织中T细胞激活能力受损与肥胖人类T细胞多样性减少和新亚型ATDC的丰富有关。我们的方法将通过检验T细胞耗竭轮廓的诱导需要不同的APC信号和T细胞中BTLA受体的诱导这一假说来确定脂肪组织T细胞因饮食肥胖而耗尽的机制。我们还将评估内源性糖皮质激素改变ATM和ATDC激活T细胞的能力，以促进疲劳的假说。完成这些目标进一步促进了对脂肪组织中产生的细胞-细胞通信网络以及它们如何促进代谢性疾病的理解。

Adipose tissue contains a network of leukocytes that respond to obesity by generating proinflammatory signals that contribute to metabolic disease. At the same time, there is strong evidence that many healthy immune responses are impaired in obesity and contribute to an increased severity of illness to many diseases that include respiratory viruses. We currently do not have a clear understanding of the mechanisms behind this dichotomy. Addressing this gap can reveal mechanisms by which a hyperactive immune system can be restrained to improve insulin resistance and can also identify mechanisms by which normal immune responses can be preserved to improve health in people with obesity. This proposal seeks to understand immune responses in adipose tissue by focusing on the mechanisms by which the innate and adaptive components of the adipose tissue immune system interact in mice and humans. Our central hypothesis is that the chronic pro-inflammatory environment generated by obesity triggers T cell and myeloid exhaustion. We further posit that the diversity of adipose tissue macrophages (ATM) and dendritic cells (ATDC) shape adipose tissue T cell responses that impair healthy resolution of adipose tissue inflammation. The premise for this hypothesis is based on the published work generated in the last grant cycle, as well as preliminary data demonstrating a impaired T cell activation capacity in obese adipose tissue from mice and humans associated with decrease diversity of T cells in obese humans and enrichment for novel subtypes of ATDC. Our approach will identify the mechanisms by which adipose tissue T cells become exhausted with dietary obesity by testing the hypothesis that the induction of T cell exhaustion profiles requires differential APC signals and the induction of BTLA receptors in T cells. We will also evaluate the hypothesis that endogenous glucocorticoids alter the ability of ATMs and ATDC to activate T cells in a way that promotes exhaustion. Completing these aims further advance the understanding of the cell-cell communication networks that are generated in adipose tissue and how they contribute to metabolic disease.