CYTOKINE GENE EXPRESSION BY CD4+ CELLS IN AGING MICE

描述（改编自申请人的摘要）： 老年人可表现出缺乏或失调的症状。 的 这个项目的长期目标是了解这些现象是如何 与成熟CD 4 + T细胞库的改变有关或由其引起。 的 胸腺退化（新的CD 4 + T细胞的来源） 与抗原（Ag）诱导的细胞分化的寿命， 在这个细胞群中发生了显著的变化，包括从一个细胞群逐渐转变为一个细胞群。 在生命早期，幼稚的、无Ag经验的细胞亚群的患病率 在晚年，分化的记忆或效应细胞亚群占优势。 我们建议使用小鼠模型和体外方法来研究影响 与年龄相关的细胞亚群频率的变化， 细胞周期、细胞死亡、细胞分化和效应细胞功能。 首先，我们将测试年龄相关的诱导表达的变化， 细胞因子和细胞因子受体通过分离的幼稚和记忆细胞亚群， 并将确定老化是否会影响细胞激活的要求， 这些子集。 辨别是否发生进一步的分化变化 在老化期间的存储器单元组内，我们将尝试识别， 计数并测试Th 0、Th 1和Th 2样记忆的反应性 细胞 在第二个系列的研究中，幼稚和记忆性CD 4+细胞将被 评估诱导细胞周期模式的年龄相关变化 进入和发展以及持续的克隆生长。 此外，CD 4 + 将检查细胞亚群在其程序中与年龄相关的差异 细胞自主死亡的可能性 这些程序与模式的关系 抗或促死亡基因的表达也将得到解决。 最后我们 将使用一种体外模型，用于研究姜黄素驱动的细胞分化， 幼稚细胞和记忆细胞容量可能与年龄有关的变化 亚群发育成Th 0-、Th 1-或Th 2-样细胞;确定是否 这些分化过程在晚年仍然是灵活的;并检查 晚期记忆细胞对神经细胞分化的影响 共同定位的幼稚细胞。 这些研究的结果应该提供 与年龄有关的代表性变化的重要信息， 不同的CD 4+细胞亚群的功能，并应产生洞察 免疫缺陷或调节异常的可能机制与改变 克隆扩增、细胞凋亡、细胞分化和效应子 在这个细胞群中发挥作用。 这些信息应有助于 老年疫苗的合理设计，以靶向初始抗原（对宿主而言为新抗原） 或记忆（先前遇到的Ag）CD 4+细胞。

DESCRIPTION (Adapted from the Applicant's abstract): The immune system of elderly humans can exhibit symptoms of deficiency or dysregulation. The long-term objective of this project is to understand how these phenomena relate to or are caused by alterations in the mature CD4+ T-cell pool. The involution of the thymus (the source of new CD4+ T-cells) in conjunction with a lifetime of antigen (Ag)-induced cell differentiation result in marked changes in this cell population, including a gradual shift from a prevalence of naive, Ag-inexperienced cell subsets in early life to a predominance of differentiated memory or effector cell subsets in late life. We propose to use the mouse model and in vitro methods to study the impact of age-related shifts in cell subset frequencies on gene programs related to cell cycle, cell death, cell differentiation, and effector cell function. First, we will test for age-related changes in the inducible expression of cytokines and cytokine receptors by isolated naive and memory cell subsets, and will determine whether aging affects the cell activation requirements of these subsets. To discern whether further differentiative change occurs within the memory cell group during aging, we will attempt to identify, enumerate, and test the responsiveness of Th0-, Th1-, and Th2-like memory cells. In a second series of studies, naive and memory CD4+ cells will be assessed for age-related changes in the patterns of inducible cell cycle entry and progression and sustained clonal growth. In addition, the CD4+ cell subsets will be examined for age-related differences in their programs for autonomous cell death. The relationship of these programs to patterns of anti- or pro-death gene expression will also be addressed. Lastly, we will use an in vitro model for cytokine-driven cell differentiation to study possible age-related changes in the capacity of naive and memory cell subsets to develop into Th0-, Th1- or Th2-like cells; to determine whether these differentiative processes remain flexible in late life; and to examine the influences of late-life memory cells on the differentiation of co-localized naive cells. Results from these studies should provide important information on age-related changes in the representation and function of distinct CD4+ cell subsets, and should yield insight into possible mechanisms of immune deficiency of dysregulation related to altered programs for clonal expansion, apoptosis, cell differentiation, and effector function in this cell group. This information should contribute to the rational design of geriatric vaccines to target naive (Ag new to the host) or memory (previously-encountered Ag) CD4+ cells.