Project 4: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

项目 4：T 细胞衰老和再生的胸腺和外周方面

• 批准号: 10226925
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 35.08万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226925
• 关键词: Adult; Age; Aging; Architecture; BMP4; Blood; CCL19 gene; Cell Aging; Cell Communication; Cell Compartmentation; Cell Maintenance; Cell Survival; Cells; Coculture Techniques; Complement; Data; Defect; Elderly; Elements; Emigrant; Endothelial Cells; Environment; Exhibits; Generations; Goals; Homeostasis; Human; IL7 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Intervention; Knowledge; Label; Lead; Longevity; Lymphatic Endothelial Cells; Maintenance; Methods; Molecular; Mus; Nature; Organism; Parabiosis; Peripheral; Plasma; Production; Program Research Project Grants; Proteomics; Publishing; Rejuvenation; Reticular Cell; Role; Signal Transduction; Spleen; Stromal Cells; Structure; Supplementation; T-Lymphocyte; TNF gene; TNFSF11 gene; Testing; Thymus Gland; TimeLine; Trans-Activators; Transgenic Organisms; Translating; Translations; Tumor Necrosis Factor Receptor; activating transcription factor 3; age related; aged; base; cell type; cytokine; immunosenescence; improved; in vivo; in vivo evaluation; lymph nodes; notch protein; novel; pre-clinical; recruit; secondary lymphoid organ; senescence; transcriptome sequencing; young adult

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. Surprisingly, the nature and the causes of these defects that impair peripheral TN cell maintenance with aging remain largely unexplored. This project will test the hypothesis that defects in the peripheral maintenance of naïve T cells in the SLO must be understood and corrected to achieve lasting immune rejuvenation. This hypothesis is based on our recently published and preliminary findings that aging leads to disorganization of lymph node (LN) architecture resulting in a dysfunctional stromal cell compartment, including the fibroblastic reticular cell (FRC) network in the T cell zone. These defects consequently led to impairment in production and presentation of key cytokines essential for optimal cell-cell interactions critical for recruitment and maintenance of TN cells. In principle, the age-related changes/defects in TN cell maintenance could be due to changes/defects in TN cells themselves, or the SLO microenvironment or the circulatory factors surrounding TN and SLO . Therefore, we will examine how aging impairs maintenance of TN cells over the lifespan at the levels of: newly produced TN cells (SA1), stromal SLO elements (SA2) and the circulatory milieu (SA3). 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 P1-3, for the ability to improve protective immunity against infection. This project will also contribute to the generation of the Immune Aging Timeline, that will correlate age-related changes in thymus, LN and peripheral T cells in mice to those in humans, providing direct preclinical data that pave the way for human T cell rejuvenation in older adults.

幼稚T细胞（TN）在胸腺中产生，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， TN数量随着年龄的增长而减少，次级淋巴细胞的外周维持机制缺陷， 器官（SLO）也显着促进免疫衰老。令人惊讶的是， 这些随着老化而损害外周TN细胞维持的缺陷在很大程度上仍未被探索。该项目将 检验SLO中幼稚T细胞的外周维持缺陷一定是 理解和纠正，以实现持久的免疫再生。这个假设是基于我们的 最近发表的初步研究结果表明，衰老导致淋巴结（LN）结构紊乱 导致功能失调的基质细胞区室，包括成纤维网状细胞（FRC）网络， T细胞区。这些缺陷导致关键细胞因子的产生和呈递受损 对于TN细胞的募集和维持至关重要的最佳细胞-细胞相互作用至关重要。 原则上，TN电池维护中与老化相关的变化/缺陷可能是由于以下方面的变化/缺陷： TN细胞本身，或SLO微环境或TN和SLO周围的循环因素。 因此，我们将研究衰老如何在以下水平上损害TN细胞在寿命期内的维持： 新产生的TN细胞（SA 1）、基质SLO元件（SA 2）和循环环境（SA 3）。一旦 缺陷解剖，我们将制定干预措施，改善外周T细胞维持在老年人 有机体这些干预措施将由核心D进行测试，单独或与胸腺再生相结合 来自P1-3的治疗，以提高对感染的保护性免疫力。该项目将 也有助于产生免疫老化时间轴，这将与年龄相关的变化， 胸腺，LN和外周T细胞在小鼠中的那些在人类中，提供直接的临床前数据，铺平了 老年人T细胞再生的方法。