Impact of aging on naive CD4 T cell function

衰老对幼稚 CD4 T 细胞功能的影响

• 批准号: 7666197
• 负责人: SUSAN L SWAIN
• 金额: $ 27.65万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666197
• 关键词: Adjuvant; Affect; Age; Aging; Animals; Antibodies; Antigens; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cell Aging; Cell Count; Cell physiology; Cells; Communicable Diseases; Defect; Drops; Elderly; Environment; Environmental Risk Factor; Exhibits; Experimental Models; Generations; Goals; Grant; Homeostasis; Immunization; In Situ; In Vitro; Individual; Infection; Inflammatory; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-7; Longevity; Lymphocyte; MHC Class II Genes; Memory; Memory B-Lymphocyte; Mus; Output; Peripheral; Population; Production; Regulation; T memory cell; T-Cell Receptor; T-Lymphocyte; Thymus Gland; Time; Transgenic Model; Transgenic Organisms; Work; Youth; age effect; age related; aged; base; cell age; cytokine; in vivo; juvenile animal; memory CD4 T lymphocyte; programs; research study; response; thymocyte; vaccine efficacy

DESCRIPTION (provided by applicant): Impact of aging on naive CD4 T cell function. We have made substantial progress in understanding age-related defects in naive CD4 T cell function, using murine T cell receptor transgenic (TCR Tg) models. We have found that decreased responsiveness to TCR stimulation in naive T cells from aged animals leads to reduced IL-2 production, proliferation and effector generation both in vitro and in vivo. In addition, memory T cells that are derived from naive CD4 T cells obtained from aged animals exhibit severe defects in proliferation, cytokine production and cognate helper function. It is quite likely that this defect contributes significantly to the reduction in vaccine efficacy observed in the elderly. Our studies have also shown that we can enhance the response of naive CD4 T cells from aged mice in vitro by the addition of exogenous IL-2 and in vivo by the use of adjuvants that induce the production of inflammatory cytokines. We have shown that a combination of these cytokines (TNFalpha, IL-1, IL-6) induces enhanced IL-2 production by aged naive cells by increasing NFKappaB activation. This, in turn, enhances primary effector generation both in vitro and in vivo. These results are exciting since they indicate that these age-related defects may be overcome by the use of adjuvants that induce higher levels of these cytokines. In this current proposal, we will continue our studies using similar experimental models. We hypothesize that the origin of the age-related defect in naive CD4 T cells is due to the fact that they are chronologically older compared to those found in younger animals. If naive T cells are chronologically older, there must be factors which regulate this. In Aim 1, we will examine the factors that may be involved in the regulation of CD4 lifespan, including other lymphocyte populations, thymic output and endogenous cytokines. In Aim 2, we will determine the effects of these age-related defects on the ability of naive CD4 T cells from aged mice to generate functional memory cells. Our overall goal is to determine what factors are involved in the genesis of age-related CD4 T cell defects, how they work, and the impact that they have on the generation of functional memory cells which are involved in protection from infectious disease.

描述（由申请人提供）：衰老对幼稚CD4 T细胞功能的影响。我们使用鼠T细胞受体转基因（TCR TG）模型在理解幼稚CD4 T细胞功能中与年龄相关的缺陷方面取得了重大进展。我们发现，来自老年动物的幼稚T细胞中对TCR刺激的反应性降低导致IL-2的产生，增殖和效应子在体外和体内产生降低。此外，源自从老年动物获得的幼稚CD4 T细胞的记忆T细胞表现出严重的缺陷，细胞因子产生和同源辅助辅助功能。这种缺陷很可能会显着促进老年人观察到的疫苗疗效的降低。 我们的研究还表明，我们可以通过添加外源性IL-2和体内通过使用诱导炎症细胞因子产生的辅助剂来增强体外老年小鼠的幼稚CD4 T细胞的反应。我们已经表明，这些细胞因子（TNFALPHA，IL-1，IL-6）的组合通过增加NFKAPPAB激活而诱导老年幼稚细胞的IL-2产生。反过来，这可以增强体外和体内的主要效应子产生。这些结果令人兴奋，因为它们表明这些与年龄相关的缺陷可以通过使用诱导较高水平的这些细胞因子的辅助因子来克服。 在当前的建议中，我们将使用类似的实验模型继续我们的研究。我们假设幼稚的CD4 T细胞中与年龄相关的缺陷的起源是由于与年轻动物相比，它们在年代学上年龄更大。如果天真的T细胞按时间顺序年龄较大，则必须有调节这一点的因素。在AIM 1中，我们将检查可能与CD4寿命有关的因素，包括其他淋巴细胞群，胸腺输出和内源性细胞因子。 在AIM 2中，我们将确定这些与年龄相关的缺陷对老年小鼠幼稚CD4 T细胞产生功能记忆细胞的能力的影响。我们的总体目标是确定与年龄相关的CD4 T细胞缺陷的起源相关的因素，它们的工作方式以及它们对涉及保护免受传染病的功能记忆细胞产生的影响。