Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

整体-摘要 传染病、癌症和自身免疫性疾病影响着数以亿计的老年人。他们 减少全球范围内的生活时间和质量，并给社会带来巨大的经济负担 以SARS-CoV-2大流行为例，在过去的50年里，它已经夺走了93.1%的受害者 年龄较大，及以上占74.4%。然而，尽管进行了数十年的研究，恢复保护性免疫 老年人仍然难以捉摸。导致年龄相关免疫功能下降的一个关键因素是 幼稚T(TN)细胞的数量和功能，以及它们的返老还童是非常可取的，以加强保护 老年人的免疫力和整体健康寿命。 这项T细胞复兴计划的更新围绕两个关键问题：(1)为什么TN 细胞数量和功能随着年龄的增长而恶化；以及(2)对此我们能做些什么？该计划的前提是 TN细胞老化是多因素的，只能通过靶向多个缺陷来解决。胸腺 退缩和由此导致的T细胞产生的下降是导致免疫衰老的最早事件。 骨髓功能的下降以及TN细胞的缺陷加剧了这种减少 外围设备的维护和运行。这些缺陷加在一起会侵蚀老年人的免疫能力。 检测和消除感染性物质和肿瘤细胞的系统，并适当防范 自身免疫力。在第一个项目期间，我们强烈确认了最初的假设，即淋巴器官 间质成分比之前认为的更早恶化，并以一种决定性的方式侵蚀免疫力， 随着年龄的增长。我们将在最初计划阶段的协同和成功的基础上再接再厉，在这一阶段中发现一个 项目正在批判性地向其他人提供科学信息，并继续寻找减少背后的机械原因 中枢和外周淋巴器官的功能随着年龄的增长而变化。然后，我们将制定综合战略，以 改善这些缺陷，提高老年人的免疫防御能力。我们的假设是机械论的 需要解剖胸腺产生和外周TN细胞维持方面的缺陷，以设计和 测试老年人T细胞年轻化的有效干预措施。 由该领域专家领导的三个综合项目，由四个尖端核心提供支持，将检验这一点 假设并实现以下计划目标：1.定义小学和中学的机械性变化 淋巴器官老化；2.测定胸腺和次级淋巴组织的内源性再生能力 生命周期中的器官间质；3.小鼠胸腺、淋巴(LN)和T细胞老化的关系 表型对人类的影响；以及4.设计和测试年轻化策略以改善胸腺生成、T细胞存活 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，并准备翻译给老年人。

OVERALL- Abstract Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults. They reduce length and quality of life across the globe and inflict a massive economic burden on society, as vividly exemplified by the SARS-CoV-2 pandemic, that has claimed 93.1% of its victims amongst those 50 years and older, and 74.4% in those 64 and older. 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, and their rejuvenation is highly desirable in order to enhance protective immunity and overall healthspan in older adults. The renewal of 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 the earliest event leading to immunosenescence. This reduction is compounded by a decline in bone marrow function, as well as by defects 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. In the first program period, we strongly confirmed our initial hypotheses that lymphoid organ stromal elements deteriorate earlier than previously thought, and in a manner to decisively erode immunity, with aging. We will build on the synergy and success of the initial program period, where discoveries in one project are critically informing science in others, and continue to identify mechanistic reasons behind reduced central and peripheral lymphoid organ function with aging. We will then develop combined strategies to ameliorate these defects to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects in both thymic production AND peripheral Tn cell maintenance is required to devise and test effective interventions for T cell rejuvenation in the elderly. Three 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 primary and secondary lymphoid organ aging; 2. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 3. Relate the progression of murine thymus, lymph node (LN) and T cell aging phenotypes to humans; and 4. Devise and test rejuvenation strategies to improve thymopoiesis, T cell survival 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 be poised for translation to older adults.