CYTOKINE GENE EXPRESSION CD4+ IN AGING MICE

描述(改编自申请者的摘要)： 老年人可能会表现出缺乏或调节失调的症状。这个 这个项目的长期目标是了解这些现象是如何 与成熟的CD4+T细胞池的改变有关或由其引起的。这个 胸腺(新的CD4+T细胞的来源)联合退化 终生抗原(Ag)诱导的细胞分化导致 这种细胞群体的显著变化，包括从 幼稚、银缺乏经验的细胞亚群在早期生命到老年的患病率 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其影响。 与年龄相关的基因程序中细胞亚群频率的年龄相关变化 细胞周期、细胞死亡、细胞分化和效应细胞功能。 首先，我们将测试与年龄相关的诱导表达的变化 由分离的幼稚和记忆细胞亚群产生的细胞因子和细胞因子受体， 并将确定衰老是否会影响细胞激活要求 这些子集。以辨别是否发生进一步的差异化变化 在老化期间的存储单元组内，我们将尝试识别， 枚举并测试Th0、Th1和Th2类内存的响应性 细胞。在第二系列研究中，幼稚和记忆性的CD4+细胞将 评估与年龄相关的诱导细胞周期模式的变化 进入和前进以及持续的克隆生长。此外，CD4+ 细胞子集将在其程序中检查与年龄相关的差异 自主性细胞死亡。这些程序与模式的关系 反死亡或支持死亡的基因表达的问题也将被讨论。最后，我们 将使用细胞因子驱动的细胞分化的体外模型来研究 幼稚细胞和记忆细胞容量的可能年龄相关性变化 亚群发展为Th0、Th1或Th2样细胞；以确定 这些分化的过程在晚年仍然是灵活的；并检查 晚年记忆细胞对神经干细胞分化的影响 共同定位的幼稚细胞。这些研究的结果应该提供 关于代表人数与年龄有关的变化的重要信息 不同的CD4+细胞亚群的功能，并应深入了解 免疫缺陷的可能机制与调节异常有关 克隆扩增、凋亡、细胞分化和效应器的程序 函数在此单元格组中。这些信息应该有助于 针对幼稚(宿主新抗原)的老年疫苗的合理设计 或记忆(先前遇到的抗原)的CD4+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.