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，这些变化与 对病原体的反应能力和对接种疫苗的有效反应的年龄相关性缺陷 在老年人身上。随着年龄的增长，先天性免疫系统和获得性免疫系统都表现出功能缺陷，其中T细胞 功能受到特别影响。T细胞功能缺陷的分子机制 然而，目前还没有完全了解。溶酶体通过自噬降解蛋白质已被证明是起作用的 通过减少受损蛋白质的积累来维持正常的细胞动态平衡的关键作用。 自噬也在调节细胞蛋白水平以响应细胞外信号方面发挥重要作用。 并与T细胞内稳态的控制有关。与本计划中的P1和P2协作 项目(PP)，我们已经证明巨型自噬和伴侣介导的自噬都在 对TCR参与的反应，并在生物能量学的维持调节中发挥关键作用 在激活的T细胞中的输出和在TCR下游的信号级联调节中分别如此。 有趣的是，这些通路的活性在衰老小鼠的T细胞中降低，其恢复导致 改善老化T细胞的激活诱导反应。此外，使用P4时，我们发现 这两条通路的活性似乎都对脂质和氧化应激做出反应，这两者都是衰老的特征 进程。 在这项建议中，我们打算阐明调节不同形式的 在T细胞中的自噬，并表征与年龄相关的自噬下降如何决定 T细胞反应缺陷的发展。我们还将研究慢性病原体、血脂和 衰老过程中的氧化应激可能导致巨噬细胞自噬和/或伴侣活性降低 随着年龄的增长介导的自噬。最后，利用小鼠模型，我们将研究恢复自噬的可能性 提高老年啮齿动物体内T细胞介导性反应的活性。 相关性：了解导致老年人免疫力下降的分子机制 生物体应该被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 这有助于提高老年人的免疫功能，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. .