MODULATION OF OX-40 AND 4-1BB FUNCTION IN AGING

老化过程中 OX-40 和 4-1BB 功能的调节

• 批准号: 2632666
• 负责人: Michael Croft
• 金额: $ 8.95万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2632666
• 关键词: B lymphocyte; CD28 molecule; CD3 molecule; CD40 molecule; T lymphocyte; aging; animal old age; antibody; biological signal transduction; cell proliferation; crosslink; cytokine receptors; gene expression; helper T lymphocyte; interleukin 12; intermolecular interaction; juvenile animal; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; ligands; lipopolysaccharides; macrophage; tissue /cell culture; tumor necrosis factor alpha

CD4 T cells play a pivotal role in the immune response primarily by directing responses of other lymphoid cells. Regulation occurs through cell-cell contact with antigen-presenting cells which directly induces signaling pathways leading to activation and function, and also results in cytokine secretion which governs the nature of the response. It is generally accepted that CD4 function in aged individuals is diminished, although the reasons and mechanisms responsible for this are not clear. Recognition of peptide/MHC complexes on APCs is a prerequisite for most aspects of CD4 function, however additional interactions between T cell co-receptors and APC accessory molecules are required for optimal cell growth, secretion of cytokines and induction of effector function. Thus, with aging, it is possible that T cells either do not express the appropriate co-receptors for efficient response, or are hypo-responsive to signaling through these molecules. An alternative, which is not mutually exclusive, is that defects exist in provision of accessory molecule help from APCs such as B cells and macrophages. The majority of studies suggest that CD28/B7, CD40L/CD40 and LFA-1/ICAM-1 interactions are critical for initial CD4 and APC activation in young individuals, whereas other molecules may be crucial for later phases of primary responses and potentially for promoting secondary responses involving memory T cells. Both already published data and our unpublished studies suggest that two ligand-receptor pairs, which are primarily expressed on T cells and APC after their initial activation, have co- stimulatory activities which can be equivalent but also distinct from the molecules above. These are members of the TNF/TNFR families, namely Ox-40- Ox-40L and 4-1BB-4-1BBL, and as such represent potential targets for defects associated with aging. The studies proposed here will assess the function and roles of these molecules in T cell and APC responses from young versus old mice. In vitro experiments will analyze naive and memory CD4 cells and assess expression of OX-40 and 4-1BB with age and whether conditions for expression of these molecules changes. We will additionally assess T cell proliferative and cytokine responses induced in responses to anti-CD3 using antibodies or Fc constructs which can ligate Ox-40 and 4- 1BB. These studies will be complemented by assessing induction and expression of Ox-40L and 4-1BBL on B cells and macrophages from aged mice, and whether cross-linking these molecules on APC is defective for inducing B cell and macrophage function compared to cells from young animals. These studies will provide novel findings with regard to T cell-APC interactions with age and may highlight ways in which hyporesponsiveness of these cells can be corrected.

CD4 T细胞在免疫反应中起关键作用，主要是 指导其他淋巴样细胞的反应。调节是通过 细胞细胞与抗原呈递细胞的接触，直接诱导 信号通路导致激活和功能，也导致 控制反应性质的细胞因子分泌。这是 普遍认为，老年个体中的CD4功能已减少， 尽管原因和机制是为此负责的。 APC上对肽/MHC复合物的识别是大多数人的先决条件 CD4功能的各个方面，但是T细胞之间的其他相互作用 最佳细胞需要共受体和APC辅助分子 生长，细胞因子的分泌和效应子功能的诱导。因此， 随着衰老，T细胞可能不表达 适当的共受体，以进行有效响应，或者对 通过这些分子发出信号。替代方案，不是相互的 独家是在提供附属分子帮助中存在缺陷 来自B细胞和巨噬细胞等APC。 大多数研究表明CD28/B7，CD40L/CD40和LFA-1/ICAM-1 相互作用对于年轻的初始CD4和APC激活至关重要 个体，而其他分子对于以后的阶段至关重要 主要响应，并有可能促进次要反应 涉及记忆T细胞。两者都已经发布了数据，我们未发表 研究表明，两个配体 - 受体对，主要是 最初激活后在T细胞和APC上表达，具有共同 刺激性活动，可以等效但也不同于 上面的分子。这些是TNF/TNFR家族的成员，即OX-40- OX-40L和4-1BB-4-1BBL，因此代表了潜在的目标 与衰老相关的缺陷。这里提出的研究将评估 这些分子在T细胞中的功能和作用和来自APC的响应的功能和作用 年轻的老鼠。体外实验将分析幼稚和记忆力 CD4细胞并评估OX-40和4-1BB随着年龄的增长的表达，以及是否是否 这些分子表达的条件发生了变化。我们还将 评估T细胞增殖和细胞因子反应在反应中引起的 使用抗体或FC构建体的抗CD3，可以将OX-40和4-结合 1BB。这些研究将通过评估归纳和 OX-40L和4-1BBL在B细胞和老年小鼠的巨噬细胞上的表达， 以及APC上的这些分子是否有缺陷诱导这些分子 与年轻动物的细胞相比，B细胞和巨噬细胞功能。这些 研究将提供有关T细胞-APC相互作用的新发现 随着年龄的增长，可能会突出这些细胞不足的方法 可以纠正。