Thymic and peripheral Aspects of T cell Aging and Rejuvenation

传染病、癌症和自身免疫性疾病影响着数以亿计的老年人，减少 全球范围内的生活长度和质量，给社会造成了巨大的经济负担。然而，尽管 几十年的研究表明，恢复老年人的保护性免疫仍然难以捉摸。一个关键因素 与年龄相关的免疫功能下降的原因之一是幼稚T(TN)细胞数量和功能的丧失。因此， 恢复T细胞功能是非常可取的，以增强保护性免疫力和整体 老年人的健康寿命。 这个T细胞复兴计划项目围绕两个关键问题：(1)为什么TN细胞数量和 功能随着年龄的增长而恶化；(2)对此我们能做些什么？编程的前提是TN小区 老化是多因素的，只能通过针对多个缺陷来解决。胸腺退缩与 由此导致的T细胞产量下降是导致免疫衰老的早期事件。这一减幅是 外周TN细胞的维持性和功能下降。这些缺陷加在一起就是 侵蚀老免疫系统检测和消除感染源和肿瘤细胞的能力，以及 妥善防范自身免疫性疾病。我们的目标是找出胸腺减少背后的机械性原因 次级淋巴器官(如淋巴)中T细胞的功能及维持和活性受损 节点，随着年龄的增长。然后，我们将制定组合策略来改善这些缺陷，以便改进 老年人的免疫防御。我们的假设是，对两个胸腺缺陷的机械解剖 需要生产和外周TN细胞维护来制定和测试有效的干预措施 用于老年人的免疫系统恢复活力。 由该领域专家领导的四个综合项目，由四个尖端核心支持，将检验这一点 假设并实现以下计划目标：1.定义胸腺和继发性胸腺的机械性变化 淋巴器官老化；2.通过比较胸腺的进展来生成人-鼠时间线， 小鼠和人的淋巴和T细胞老化；3.测定小鼠和人的内源性再生能力 胸腺和次级淋巴器官基质的寿命；4.设计和测试年轻化策略以 改善胸腺生成和外周T细胞的维持和功能，从而增强保护性免疫。 在这段支持期内，上述目标将提供丰富的基本知识，这些知识将转化为 临床前模型，并在人-鼠时间线的帮助下，准备翻译给老年人。

Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults, reducing length and quality of life across the globe and inflicting a massive economic burden on society. Yet, despite decades of research, restoring protective immunity in older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of naïve T (TN) cell numbers and function. Thus, rejuvenation of T cell function is highly desirable in order to enhance protective immunity and overall healthspan in older adults. This T cell Rejuvenation Program Project is centered on two key questions: (1) why do TN cell numbers and function deteriorate with age and; (2) what can be done about it? The premise of the program is that TN cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and the resulting decline in T cell production is an early event leading to immunosenescence. This reduction is compounded by a decline in TN cell maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against autoimmunity. Our goal is to identify mechanistic reasons behind reduced thymic function as well as impaired maintenance and activity of T cells in secondary lymphoid organs, such as lymph nodes, with aging. We will then develop combined strategies to ameliorate these defects in order to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects to both thymic production AND peripheral TN cell maintenance is required to formulate and test effective interventions for immune system rejuvenation in the elderly. Four integrated projects led by experts in the field, supported by four cutting-edge cores, will test this hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in thymic and secondary lymphoid organ aging; 2. Generate the Human-Mouse Timeline by comparing the progression of thymus, lymph node and T cell aging in mice and humans; 3. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 4. Devise and test rejuvenation strategies to improve thymopoiesis and peripheral T cell maintenance and function, so as to enhance protective immunity. Over this support period, the above goals will provide a wealth of basic knowledge that will be translated to preclinical models and, with the help of the Human-Mouse Timeline, be poised for translation to older adults.