Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

总体-摘要 传染病、癌症和自身免疫性疾病影响着数亿老年人。他们 缩短了地球仪的寿命，降低了生活质量，给社会造成了巨大的经济负担， 以SARS-CoV-2大流行为例，在这50年中，93.1%的受害者死亡， 64岁及以上的占74.4%。然而，尽管经过几十年的研究，恢复保护性免疫力， 老年人仍然难以捉摸。导致与年龄相关的免疫力下降的一个关键因素是免疫力的丧失。 幼稚T（Tn）细胞的数量和功能，以及它们的复壮是非常需要的，以增强保护性T（Tn）细胞的功能。 老年人的免疫力和整体健康状况。 这个T细胞返老还童计划项目的更新围绕两个关键问题：（1）为什么Tn 随着年龄的增长，细胞的数量和功能会下降;（2）对此可以做些什么？该计划的前提是 Tn细胞老化是多因素的，并且只能通过针对多个缺陷来解决。胸腺 退化和由此导致的T细胞产生的下降是导致免疫衰老的最早事件。 这种减少与骨髓功能的下降以及Tn细胞的缺陷有关。 在外围的维护和功能。这些缺陷联合收割机削弱了老年人免疫系统的能力， 系统，以检测和消除感染因子和肿瘤细胞，并适当地防止 自身免疫在第一个项目期间，我们强烈证实了我们最初的假设，即淋巴器官 基质成分比以前认为的更早地恶化，并且以决定性地侵蚀免疫力的方式， 随着年龄的增长。我们将在初始计划期的协同作用和成功的基础上再接再厉，将发现集于一体 项目正在批判性地告知其他科学，并继续确定减少背后的机械原因 中枢和外周淋巴器官功能随年龄的变化。然后，我们将制定综合战略， 改善这些缺陷，以提高老年人的免疫防御。我们的假设是， 需要对胸腺产生和外周Tn细胞维持中的缺陷进行解剖， 测试老年人T细胞再生的有效干预措施。 由该领域专家领导的三个综合项目，在四个尖端核心的支持下，将对此进行测试 假设并实现以下计划目标：1。定义主要和次要的机械变化 淋巴器官老化; 2.测定胸腺和次级淋巴细胞的内源性再生能力 器官间质在整个寿命期间; 3.小鼠胸腺、淋巴结（LN）和T细胞老化的进展 人类的表型;以及4.设计和测试再生策略，以改善胸腺生成，T细胞存活 以及外周T细胞的维持和功能，从而增强保护性免疫。 在此支持期间，上述目标将提供丰富的基础知识，这些知识将转化为 临床前模型，并准备转化为老年人。

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.