Peripheral T cell maintenance defects with aging

项目3-摘要 原始T细胞(TN)是在胸腺中产生的，但需要外周机制来维持其 动态平衡和功能。这个项目的前提是，虽然胸腺退缩是导致 TN数量随增龄减少，次级淋巴器官外周维持机制缺陷 (SLO)也对免疫衰老有显著贡献。事实上，在过去的项目期内，我们有 证明在TN细胞的外周维持中未纠正的缺陷可以强烈地破坏 恢复活力的胸腺唤醒T细胞产生的益处。我们进一步确定了一个精确的 不同类型SLO退行性结构和功能改变的时间顺序。 这一更新应用将继续剖析SLO衰老的分子和细胞基础 和再生。根据变化的顺序和支持TN细胞和TN之间的串扰的证据 SLO间质，我们假设胸腺产生的TN细胞减少减少了SLO的营养信号 间质，导致最初的间质生态位和网络解体，进而剥夺TN细胞 生命营养信号，并启动TN细胞和SLO恶化的负前馈循环 间质反应。我们的具体目标是： SA1.IL-7复合体和增龄对淋巴结间质分子变化的影响 返老还童，使用体外和体内方法的分级来测试由以下方法确定的候选人的管道 小型阵列和scRNASeq方法在过去的支持期间；以及SA2。要剖析内在的和 SLO间质细胞的外源性年龄相关缺陷及TN：基质串扰在LN中的作用 动态平衡与衰老，通过检测氧化应激、衰老细胞积累、持久性的作用 LN/SLO老化过程中TN细胞内流和自然多菌素暴露(对宠物店小鼠)。 一旦缺陷被解剖，我们将制定出改善外周T细胞的干预措施 老年生物体的维护。这些干预措施将由Core D单独或与 来自P1和2的胸腺年轻化疗法，用于提高保护性免疫能力 感染。以及来自A和B核心的强大分析管道，以及人类分子靶标 经Core C验证，这将使小鼠T细胞和淋巴器官老化的年龄相关变化与 在人类中，这将提供直接的临床前数据，有望为人类T细胞铺平道路 老年人的年轻化。

PROJECT 3- Abstract Naïve T cells (Tn) are produced in the thymus, but require peripheral mechanisms to maintain their homeostasis and function. The premise of this project is that, while thymic involution is a proximal cause of reduced Tn numbers with aging, defects in peripheral maintenance mechanisms in secondary lymphoid organs (SLO) also significantly contribute to immunosenescence. Indeed, in the past project period we have demonstrated that uncorrected defects in peripheral maintenance of Tn cells can powerfully undermine the benefits of reawakening T cell production by the rejuvenated thymus. We further pinpointed a precise chronological sequence of degenerative structural and functional changes in different SLO. This renewal application will continue to dissect mechanistic molecular and cellular basis of SLO aging and regeneration. Based on the order of changes and the evidence supporting cross-talk between Tn cells and SLO stroma, we hypothesize that reduced thymic production of Tn cells reduces trophic signals to SLO stroma, leading to initial stromal niche and network disorganization, that in turn deprives Tn cells of vital trophic signals and initiates a negative feed-forward loop of deterioration in both Tn cell and SLO stromal responses. Our specific aims are: SA1. To elucidate molecular changes in lymph node stroma with aging and IL-7 complex rejuvenation, using a hierarchy of in vitro and in vivo approaches to test a pipeline of candidates identified by miniarray and scRNASeq approaches in the past support period; and SA2. To dissect the intrinsic and extrinsic age-related defects in SLO stromal cells and the role of Tn:stromal crosstalk in LN homeostasis with aging, by examining the roles of oxidative stress, senescent cell accumulation, persistent Tn cell influx and natural polymicrobial exposure (to pet store mice) in LN/SLO aging. Once the defects are dissected, we will formulate interventions that improve peripheral T cell maintenance in aged organisms. These interventions will be tested by Core D, individually or combined with thymic rejuvenation treatments coming from P1&2, for the ability to improve protective immunity against infection. Together with powerful analytical pipelines from Cores A&B, as well as human molecular target verification by Core C, that will correlate age-related changes in mouse T cell and lymphoid organ aging to those in humans, this will provide direct preclinical data that are expected to pave the way for human T cell rejuvenation in older adults.