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

项目3 摘要 胸腺相关的胸腺退化在T细胞介导的免疫的恶化中起关键作用， 从而增加了老年人对传染病、癌症的易感性， 自身免疫退化的胸腺产生较少的幼稚T细胞，从而损害保护性T细胞的产生。 对新遇到的抗原的免疫反应;此外，老年胸腺环境的缺陷 可能导致无效的中枢耐受诱导，可能导致 随着年龄的增长，胸腺细胞的成熟依赖于不可或缺的存活、分化和分化。 由异质性胸腺基质细胞提供的增殖线索。胸腺基质恶化 隔室在很大程度上负责与年龄相关的胸腺退化。然而，底层的细胞和 导致基质下降的分子机制以及对T细胞发育和选择的精确影响 仍然未知。项目3的前提是，衰老的胸腺基质细胞的功能下降是由于 改变的基因表达损害T细胞分化的多个阶段。我们假设， 胸腺基质细胞中与年龄相关的特定分子和细胞缺陷将为设计 恢复胸腺功能的策略，以在整个生命周期中维持健康的T细胞区室。在Aim中 1，我们将确定在胸腺退化过程中早期胸腺祖细胞（ETP）的丢失是否是由于年龄- ETP小生境数量和/或质量的相关下降，以及有效的反弹疗法是否 恢复ETP生态位。在目标2中，我们将测试的假设，作为胸腺上皮细胞（TEC） 隔室恶化，胸腺细胞不再有效地招募到髓质中，并且阴性 选择受损，这可能会使自身反应性T细胞逃逸。在目标3中，我们将执行转录 分析以鉴定TEC中表达的调节TEC稳态的年龄调节基因，并支持 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 老化小鼠TEC和内皮细胞（EC）以及相应的人胸腺细胞的分子特征数据 数据（核心C）至人-小鼠时间轴（P1）。为了分析ETP生态位数量，我们将与 核心B，还将提供全面的生物统计支持。年龄相关变化分析 将（通过核心A）将TEC和EC中影响胸腺的EC变化与P2的数据整合 反弹此外，我们将比较胸腺退化的分子和细胞驱动因素与衰老相关的 淋巴结（P4）中识别的变化，以便于设计新的策略， 外周淋巴器官（核心D）。因此，P3中产生的结果对于实现总体目标不可或缺。 阐明胸腺和外周免疫衰老的机制， 设计和评估合理的治疗策略，以恢复T细胞区室。

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.