Project 3: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

项目3 摘要 与年龄相关的胸腺退化在T细胞介导的免疫恶化中起着关键作用。 从而增加了老年人对传染病、癌症和 自身免疫力。退化的胸腺产生较少的幼稚T细胞，从而影响保护性T细胞的生成 对新发现的抗原的免疫反应；此外，老年胸腺环境中的缺陷 可能导致低效的中枢耐受诱导，潜在地导致 自身免疫力随年龄增长。胸腺细胞的成熟依赖于不可或缺的生存、分化和 异种胸腺基质细胞提供的增殖信号。胸腺间质变性 脑室是与年龄相关的胸腺退化的主要原因。然而，潜在的蜂窝和 间质衰退的分子机制及其对T细胞发育和选择的确切影响 仍然不为人所知。项目3的前提是老化的胸腺基质细胞的功能下降是由于 基因表达改变，损害多个阶段的T细胞分化。我们假设辨认 胸腺基质细胞中特定的分子和细胞年龄相关缺陷将为设计 恢复胸腺功能的策略，以在整个生命周期内保持健康的T细胞隔间。在AIM 1，我们将确定胸腺退化过程中早期胸腺祖细胞(ETP)的丧失是否由于年龄- ETP利基的数量和/或质量的相关下降，以及反弹疗法是否有效 恢复ETP利基市场。在目标2中，我们将检验如下假设：作为胸腺上皮细胞(TEC) 间室恶化，胸腺细胞不再有效地被招募到髓质，并且阴性 选择受损，这可能会导致自身反应性T细胞逃逸。在目标3中，我们将执行转录 识别在TEC中表达的调节TEC动态平衡和支持TEC的年龄调节基因 胸腺生成。随后的功能分析将确定候选基因对胸腺功能的影响。 P3与所有其他项目和核心有多个交叉点。例如，我们将提供 衰老小鼠TEC和内皮细胞及相应的人胸腺分子特征数据 数据(核心C)到人-鼠时间线(P1)。对于ETP利基数量的分析，我们将与 核心B，它还将在整个过程中提供一般生物统计学支持。年龄相关变化的分析 在TEC和EC中，将(通过核心A)与P2中关于EC中影响胸腺的变化的数据进行整合 抢篮板球。此外，我们还将比较与衰老相关的胸腺退化的分子和细胞驱动因素。 在淋巴结中发现的变化(P4)，以促进设计新的策略来恢复中央和 外周淋巴器官(核心D)。因此，在P3中产生的结果是实现总体 阐明胸腺和外周免疫衰老机制的计划目标，以及 设计和评估合理的治疗策略以恢复T细胞隔间的活力。

PROJECT 3 ABSTRACT Age-associated thymic involution plays a critical role in the deterioration of T cell-mediated immunity, thereby contributing to the increased susceptibility of older individuals to infectious disease, cancer, and autoimmunity. The involuted thymus produces fewer naïve T cells impairing the generation of protective immune responses against newly encountered antigens; moreover, defects in the aged thymic environment may lead to inefficient central tolerance induction, potentially contributing to the increased incidence of autoimmunity with age. Thymocyte maturation depends on indispensable survival, differentiation, and proliferative cues provided by heterogeneous thymic stromal cells. Deterioration of the thymic stromal compartment is largely responsible for age-associated thymic involution. However, the underlying cellular and molecular mechanisms resulting in stromal decline and the precise impact on T cell development and selection remain unknown. The premise of Project 3 is that declining function of aging thymic stromal cells is due to altered gene expression that impairs multiple stages of T cell differentiation. We hypothesize that identifying specific molecular and cellular age-associated defects in thymic stromal cells will provide a basis for devising strategies to restore thymic function to maintain a healthy T cell compartment throughout the lifespan. In Aim 1, we will determine if the loss of early thymocyte progenitors (ETP) during thymic involution is due to an age- associated decline in the quantity and/or quality of ETP niches, and whether effective rebound therapies restore the ETP niche. In Aim 2, we will test the hypothesis that as the thymic epithelial cell (TEC) compartment deteriorates, thymocytes are no longer efficiently recruited into the medulla, and negative selection is impaired, which could allow escape of autoreactive T cells. In Aim 3, we will perform transcriptional profiling to identify age-regulated genes expressed in TEC that regulate TEC homeostasis and support of thymopoiesis. Subsequent functional analysis will determine the impact of candidate genes on thymic function. P3 has multiple points of intersection with all other Projects and Cores. For example, we will provide data on molecular signatures of aging mouse TEC and endothelial cells (EC) and corresponding human thymic data (Core C) to the Human-Mouse Timeline (P1). For analysis of ETP niche quantity, we will collaborate with Core B, which will also provide general Biostatistics support throughout. Analysis of age-associated changes in TEC and EC will be integrated (through Core A) with data from P2 on changes in EC that impact thymic rebound. In addition, we will compare molecular and cellular drivers of thymic involution with aging-associated changes identified in lymph nodes (P4), to facilitate design of novel strategies to rejuvenate both central and peripheral lymphoid organs (Core D). Thus, the results generated in P3 are integral to achieving the overall Program goals of elucidating mechanisms responsible for thymic and peripheral immunosenescence, and devising and evaluating rational therapeutic strategies to rejuvenate the T cell compartment.