T CELL MATURATION AND THYMIC ACTIVITY IN THE AGED

描述(改编自申请人的摘要)：老化导致 免疫活力下降，T淋巴细胞发生显著变化 活动。这些功能变化是由于 随着年龄的增长，外周T细胞室的变化。因此，老年人 动物的外周T细胞隔间由CD4+T细胞组成， 在表型和功能上都与杨氏病不同 动物。据推测，这些成分变化发生在 随着年龄的增长，由于终生接触抗原而逐渐丧失 来自胸腺的新分化的幼稚细胞的输入。然而， 最近的数据表明，老龄化环境可能起到更积极的作用 在指导“新的”T细胞的成熟方面比之前所认识的要好。 因此，在老年骨髓嵌合动物中，大多数新生的 正在崛起的CD4+T细胞具有老年T细胞特有的“记忆”标志 细胞并具有衰老的功能特征。本提案将 检验老年胸腺网和/或外周的假设 微环境能够指导新分化T细胞的成熟 细胞向CD44hiCD45RBloL-选择素Lo表型转化，从而产生 淋巴因子谱包括IL-2、IL-4、IL-5和g-干扰素， 具有大多数老化的CD4+T细胞的特征。这样做的目的是 建议是：鉴定在老年骨髓中发现的CD4+T细胞 嵌合体，将它们的表型和功能与匹配的亚集进行比较 取自未经处理的幼龄和老年小鼠，以确定其相对 胸腺和外周微环境对心脏功能的影响 CD4+Th亚群的成熟，并探索几种可能的 记忆样T细胞形成的可能机制 老年嵌合体中淋巴因子环境、B7-1和B7-2的表达 和分布，以及胸腺后成熟的CD4+群体的扩张。它 预计结果将促进我们对 衰老对T细胞分化的影响允许设计更多 有效手段操控免疫系统实现保护性 老年人和其他免疫功能减退的人的免疫 例如骨髓移植患者和化疗接受者。

DESCRIPTION (Adapted from the Applicant's Abstract): Aging results in a decline in immune vigor with significant changes occurring in T lymphocyte activity. These functional changes occur as a result of compositional shifts in the peripheral T cell compartment with age. Thus, the aged animals' peripheral T cell compartment is comprised of CD4+ T cells which are phenotypically and functionally distinct from those found in young animals. It was hypothesized that these compositional changes occur progressively with age due to a lifetime of antigenic exposure, and a loss of input of newly differentiated naive" cells from the thymus. However, recent data suggests that the aged environment may play a more active role in directing the maturation of "new" T cells than previously appreciated. Thus, in aged bone marrow chimeric animals, the majority of the newly arising CD4+ T cells bear the characteristic "memory" markers of aged T cells and have aged functional characteristics. The present proposal will test the hypothesis that the aged thymic reticulum and/or peripheral microenvironment is able to direct the maturation of newly differentiating T cells towards the CD44hiCD45RBloL-selectinlo phenotype which produces a spectrum of lymphokines including IL-2, IL-4, IL-5, and g-IFN, characteristic of the majority of aged CD4+ T cells. The objectives of this proposal are to: characterizing the CD4+ T cells found in aged bone marrow chimeras, comparing their phenotype and function with matched subsets derived from unmanipulated young and aged mice, to determine the relative contribution of the thymic and the peripheral microenvironment to the maturation of the CD4+ Th subpopulations, and to explore several possible mechanisms which might contribute to the appearance of memory-like T cells in the aged chimeras including, lymphokine milieu, B7-1 and B7-2 expression and distribution, and post-thymic expansion of mature CD4+ populations. It is anticipated that the results shall advance our understanding of the consequence of aging on T cell differentiation allowing the design of more effective means to manipulate the immune system to achieve protective immunity both in aged individuals and others with diminished immune function such as bone marrow transplant patients, and chemotherapy recipients.