Peripheral T cell maintenance defects with aging

项目3-摘要 幼稚T细胞（Tn）是在胸腺中产生的，但需要外周机制来维持其免疫功能。 稳态和功能。这个项目的前提是，虽然胸腺退化是一个近端的原因， 随着年龄的增长，Tn数量减少，次级淋巴器官的外周维持机制缺陷 (SLO)也显著促进免疫衰老。事实上，在过去的项目期间， 证明了未纠正的Tn细胞外周维持缺陷可以有力地破坏 通过恢复活力的胸腺重新唤醒T细胞产生的益处。我们进一步确定了 不同SLO的退行性结构和功能变化的时间顺序。 这项更新申请将继续剖析SLO老化的分子和细胞机制基础 和再生。基于变化的顺序和支持Tn细胞和细胞间串扰的证据， SLO间质，我们假设胸腺Tn细胞产生的减少减少了SLO的营养信号 基质，导致初始基质龛和网络解体，这反过来又剥夺了Tn细胞的 重要的营养信号，并启动负前馈循环的恶化，在Tn细胞和SLO 基质反应我们的具体目标是： SA 1.阐明淋巴结间质随衰老和IL-7复合物的分子变化 复壮，使用体外和体内方法的层次结构来测试通过以下方法确定的候选物的管道 在过去的支持期内，微阵列和scRNASeq方法;以及SA 2。剖析内在的， SLO基质细胞的外源性年龄相关缺陷和Tn：基质串扰在LN中的作用 通过研究氧化应激、衰老细胞积累、持续性衰老和衰老的作用， LN/SLO老化中的Tn细胞流入和天然多微生物暴露（对宠物店小鼠）。 一旦缺陷被解剖，我们将制定干预措施，改善外周T细胞 在老化的生物体中维持。这些干预措施将由核心D单独或结合 来自P1和P2的胸腺再生治疗，用于提高保护性免疫力， 感染与Cores A和B的强大分析管道以及人类分子靶点一起， 核心C的验证，这将使小鼠T细胞和淋巴器官老化中与年龄相关的变化与 这将提供直接的临床前数据，预计将为人类T细胞 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.