Metabolic alterations in age-associated dendritic cell dysfunction

衰老与进行性免疫功能障碍有关，导致效应器反应迟钝和 对传染病和癌症的易感性增加。一个重要的贡献者减少了 反应性是指最强大的抗原提呈细胞--树突状细胞(DC)的功能受损。一个 DC功能的关键方面是它们将与细胞相关的抗原“交叉呈递”到CD8+T细胞的能力，这一过程 需要交叉启动CD8+T细胞对肿瘤或细胞内病原体的反应。然而，其效果是 原代DC对细胞相关AGS的获取、处理和呈现的老化几乎没有 已经研究过了。 我们最近发现，衰老显著降低了大脑的交叉呈现和交叉启动能力。 在执行这一重要任务时，DC亚群是最有效的(CD8DC和α树突状细胞)。年迈的区议会 表达正常的MHC I类水平，并能够将CD8+T细胞激活为可溶性多肽，但它们 细胞相关物质的吞噬功能明显受损。 从机制上讲，生物能量状态，特别是线粒体活性和膜电位(Δψm)， 已证明可调节DC的吞噬能力。线粒体功能在小鼠中受到严重影响 Cd8α或mcDC表现为Δψm降低，atp周转率和偶联效率降低，基线降低。 氧化磷酸化，以及更大的质子泄漏和ROS产生。陈列旧猕猴CD1c+DC 相似的缺陷，表现出跨物种的功能障碍。年轻树突状细胞的药理操纵以模拟 老年人的代谢表型显著阻碍了它们的吞噬和交叉激发能力，但在体外 NAC对ROS的清除显著逆转了老年人的交叉呈现缺陷！集散控制系统。我们的相互关联 假设是：(1)与年龄相关的线粒体活性变化会减少吞噬和交叉呈现。 小鼠树突状细胞的活性；以及(2)改善线粒体的活性将增强DC的功能及其作为 老年人的抗肿瘤治疗。 这些假设将在以下三个目标中得到检验。目标1将确定潜在的机制 衰老小鼠树突状细胞线粒体适合性降低。我们将剖析老化对DC使用的影响，以及 依赖特定的碳源和代谢途径来满足他们的能源需求。此外，我们 将评估观察到的代谢变化是否源于DC前体缺陷，即老年人 他们区分的环境，或两者的组合。目标2将决定是否改进 衰老小鼠树突状细胞线粒体活性增强其诱导更强T细胞应答的能力 Aim 3将研究改善线粒体功能对它们的影响 使用已建立的交叉呈现体内模型诱导抗肿瘤反应的能力。 好了！

Aging is associated with progressive immune dysfunction, resulting in blunted effector responses and increased susceptibility to infectious disease and cancers. A significant contributor to this decreased responsiveness is the impaired functionality of the most potent Ag-presenting cells, the dendritic cells (DCs). A key aspect of DC function is their capacity to “cross-present” cell-associated Ag to CD8+T cells, a process that is required to cross-prime CD8+T cell responses against tumors or intra-cellular pathogens. However, the effect of aging on the acquisition, processing, and presentation of cell-associated Ags by primary DCs has barely been studied. We recently uncovered that aging significantly reduced the cross-presenting and cross-priming capacity of the DC subsets the most efficient at carrying out this important task (CD8αDCs and merocytic DCs). Aged DCs expressed normal MHC class I levels and were able to prime CD8+T cells to soluble peptides, but they were strikingly impaired in terms of phagocytosis of cell-associated materials. Mechanistically, the bio-energetic status, notably mitochondrial activity and membrane potential (Δψm), has been shown to regulate DC phagocytic capacity. Mitochondrial function was profoundly affected in murine CD8α or mcDCs, as shown by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and ROS production. Old macaque CD1c+ DCs displayed similar defects, demonstrating dysfunction across species. Pharmacologic manipulation of young DCs to mimic the aged metabolic phenotype significantly impeded their phagocytic and cross-priming capacity, but in vitro scavenging of ROS by NAC significantly reversed the cross-presentation defect of aged! DCs. Our inter-related hypotheses are: (1) age-related changes in mitochondrial activity diminish the phagocytic and cross-presenting activity of murine DCs; and (2) improving mitochondrial activity will boost DC functionality and their potential as anti-tumor therapeutics in the elderly. These hypotheses will be tested in the following 3 aims. Aim 1 will identify the mechanisms underlying decreased mitochondrial fitness in aged murine DCs. We will dissect the effect of aging on DC use of, and dependence on, specific carbon sources and metabolic pathways to meet their energy needs. Moreover, we will assess whether the observed metabolic changes result from defects in the DC precursor, the aged environment in which they differentiate, or a combination of both. Aim 2 will determine whether improving mitochondrial activity of aged murine DCs increases their capacity to induce more vigorous T cell responses to cell-associated Ags in vitro, while Aim 3 will study the effect of improving mitochondrial function on their capacity to induce anti-tumor responses using well-established in vivo models of cross-presentation. !