Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

脂肪组织包含一个白细胞网络，通过产生促进代谢疾病的促炎信号来应对肥胖。与此同时，有强有力的证据表明，许多健康的免疫反应在肥胖中受到损害，并导致包括呼吸道病毒在内的许多疾病的严重程度增加。我们目前对这种二分法背后的机制还没有一个清晰的认识。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，也可以确定保持正常免疫反应以改善肥胖人群健康的机制。本提案旨在通过关注小鼠和人类脂肪组织免疫系统的先天和适应性成分相互作用的机制来理解脂肪组织中的免疫反应。我们的中心假设是肥胖产生的慢性促炎环境触发T细胞和骨髓衰竭。我们进一步假设脂肪组织巨噬细胞（ATM）和树突状细胞（ATDC）的多样性塑造了脂肪组织T细胞反应，损害了脂肪组织炎症的健康解决。这一假设的前提是基于上一个拨款周期中发表的工作，以及初步数据表明，小鼠和人类肥胖脂肪组织中T细胞激活能力受损与肥胖人类T细胞多样性降低和ATDC新亚型的丰富相关。我们的方法将通过验证以下假设来确定脂肪组织T细胞因饮食性肥胖而耗竭的机制：T细胞耗竭谱的诱导需要不同的APC信号和T细胞中BTLA受体的诱导。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，从而促进T细胞衰竭的假设。完成这些目标进一步推进了对脂肪组织中产生的细胞-细胞通信网络及其如何导致代谢疾病的理解。

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.