CD8 T CELL ACTIVATION IN INFLAMMATORY CNS DISEASE

炎症性中枢神经系统疾病中的 CD8 T 细胞激活

• 批准号: 2891467
• 负责人: GUY J BUCKLE
• 金额: $ 10.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891467
• 关键词: CD28 molecule; CD8 molecule; DNA binding protein; T cell receptor; biological signal transduction; calcium flux; cell proliferation; central nervous system disorders; clinical research; clone cells; cytokine receptors; cytotoxic T lymphocyte; cytotoxicity; enzyme activity; flow cytometry; human T cell lymphotropic virus type 1; human subject; immunoregulation; interleukin 2; leukocyte activation /transformation; phosphorylation; receptor expression; spastic paralysis; telomerase; virus protein

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic viral disease of the central nervous system (CNS) characterized by profound immunodysregulation and by a remarkably high frequency of virally reactive CD8+ T cells in the blood and spinal fluid. Based on the expression of surface molecules on CD8 T cells and on their relative telomeric length, it appears that CD11b+CD28- T cells and CD11b-/CD28+ T cells may define reciprocal subsets of CD8+ T cells. CD28 appears to identify a naive population of CD8+ T cells which have telomere lengths equivalent to CD4+ T cells from the same individual and can be stimulated to differentiate into cytotoxic or other effector cells by appropriate costimulation through the TCR/CD3 complex and CD28. CD28-/CD11b+ T cells, on the other hand, appear to represent an oligoclonally expanded memory phenotype, which may contain virally specific CD8+T cells, and which display shortened telomeres in comparison to their CD28+ counterparts in the same individual, thus implying many more rounds of division in the course of their oligoclonal expansion. However, the investigation of these subsets has been hampered by the difficulty in generating T cell clones. We have established conditions to routinely generate CD8+ T cell clones of both functional subsets, which allows us for the first time to investigate the functional differences between these subsets at the biochemical level. We have demonstrated differences in T cell activation and cytokine secretion between the subsets in normal individuals, both in freshly isolated PBMC and at the clonal level. We hypothesize that CD8+/CD11b+ T cells represent a preactivated and virally specific population in vivo. Investigation of this subset at the molecular level will provide important information regarding human CD8+ T cell biology, both in HAM/TSP as well as in other chronic viral infections, such as HIV disease, and in normal immune responses.

HTLV-I 相关脊髓病/热带痉挛性截瘫 (HAM/TSP) 是 中枢神经系统 (CNS) 的慢性病毒性疾病 其特点是严重的免疫失调和非常高的 血液和脊髓中病毒反应性 CD8+ T 细胞的频率 体液。 基于CD8 T细胞表面分子的表达和 根据其相对端粒长度，CD11b+CD28- T 细胞似乎 CD11b-/CD28+ T 细胞可以定义 CD8+ T 细胞的相互亚群。 CD28 似乎可以识别初始的 CD8+ T 细胞群，这些细胞具有 端粒长度相当于同一个体的 CD4+ T 细胞 可以被刺激分化成细胞毒性或其他效应子 通过 TCR/CD3 复合物和 CD28 进行适当的共刺激。 另一方面，CD28-/CD11b+ T 细胞似乎代表 寡克隆扩展记忆表型，其中可能含有病毒 特定的 CD8+T 细胞，并显示缩短的端粒 与同一个体中的 CD28+ 对应物进行比较，因此 意味着在寡克隆过程中需要进行更多轮的分裂 扩张。 然而，对这些子集的调查已经 由于难以产生 T 细胞克隆而受到阻碍。 我们有 建立了常规生成两者的 CD8+ T 细胞克隆的条件 功能子集，这使我们能够第一次研究 这些子集在生化方面的功能差异 等级。 我们已经证明了 T 细胞激活和 正常个体亚群之间的细胞因子分泌，无论是 新鲜分离的 PBMC 和克隆水平。 我们假设 CD8+/CD11b+ T 细胞代表预激活的病毒特异性 体内群体。在分子水平上研究这个子集 将提供有关人类 CD8+ T 细胞生物学的重要信息， 在 HAM/TSP 以及其他慢性病毒感染中，例如 HIV 疾病以及正常的免疫反应。