Role of Autophagy in T Cell Function and Immunosenescence (Project 3)

项目摘要 免疫衰老定义了与年龄相关的免疫系统的变化， 对病原体的反应能力和对疫苗接种的有效反应能力的年龄依赖性缺陷 在老年人中。先天免疫系统和适应性免疫系统都随着年龄的增长而表现出功能缺陷，T细胞的功能随着年龄的增长而增强。 功能受到特别影响。导致T细胞功能缺陷的分子机制 然而，还没有完全理解。通过自噬作用的蛋白质溶酶体降解已经被证明是 通过减少受损蛋白质的积累，在维持正常细胞稳态中起关键作用。 自噬还在响应细胞外信号的细胞蛋白水平的调节中起重要作用， 并且与T细胞稳态的控制有关。在本项目中与P1和P2合作 项目（PP），我们已经表明，巨自噬和伴侣介导的自噬都被激活， 在调节维持生物能量学方面发挥关键作用 分别在活化的T细胞中和TCR下游的信号级联调节中的输出。 有趣的是，这些途径的活性在来自老年小鼠的T细胞中降低，并且其恢复导致 改善老化T细胞中活化诱导应答。此外，与P4一起工作，我们发现， 这两种途径的活性似乎对脂质和氧化应激反应，这两种应激都是衰老的特征。 过程 在这个建议中，我们打算阐明调节不同形式的蛋白质的分子机制。 自噬在T细胞中的作用，并描述了自噬的年龄相关性下降如何决定T细胞中的自噬。 T细胞反应缺陷的发展。我们还将研究如何增加慢性病原体，脂质和 衰老中的氧化应激可能导致巨自噬和/或伴侣蛋白活性降低 介导的自噬。最后，利用小鼠模型，我们将研究恢复自噬的可能性， 活性，以改善体内T细胞介导的应答。 相关性：了解老年人免疫力下降的分子机制 微生物应该证明在开发旨在恢复正常的新的治疗干预方面是有价值的。 免疫功能，从而降低老年人的发病率和死亡率。 .

Project Summary Immunosenescence defines the changes in the immune system associated with age that are responsible for the age-dependent defects in the ability to respond to pathogens and develop effective responses to vaccination in the elderly. Both the innate and the adaptive immune system show functional defects with age, with T cells' function being specially affected. The molecular mechanisms that are responsible for defective T cell function are however not yet fully understood. Lysosomal degradation of proteins via autophagy has been shown to play a key role in maintaining normal cell homeostasis by reducing the accumulation of damaged proteins. Autophagy also plays an important role in the regulation of cell protein levels in response to extracellular signals, and has been implicated in the control of T cell homeostasis. In collaboration with P1 and P2 in this Program Project (PP), we have shown that macroautophagy and chaperone mediated autophagy are both activated in response to TCR engagement and play key roles in the regulation of the maintenance of the bioenergetics output in activated T cells and in the regulation of signaling cascades downstream of the TCR, respectively. Interestingly the activity of these pathways is reduced in T cells from aged mice and its restoration leads to improve activation-induced responses in aged T cells. Furthermore, working with P4 we have found that the activity of both pathways appears to respond to lipid and oxidative stress, both characteristic of the aging process. In this proposal we intend to elucidate the molecular mechanisms that regulate the different forms of autophagy in T cells and characterize how the age-associated decline in autophagy may determine the development of deficient T cell responses. We will also study how increased chronic pathogen, lipid and oxidative stress in aging may contribute to the decreased activity of macroautophagy and/or chaperone mediated autophagy with age. Finally, using mouse models, we will study the possibility ofrestoring autophagic activity in old rodents to improve T cell-mediated responses in vivo. Relevance: Understanding the molecular mechanism that are responsible for reduced immunity in old organisms should prove valuable in the development of new therapeutic interventions aimed at restoring normal immune function and therefore reduce morbidity and mortality in the elderly. .