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: 6187652
• 负责人: GUY J BUCKLE
• 金额: $ 11.77万
• 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/6187652
• 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相关的脊髓病/热带痉挛性瘫痪（HAM/TSP）是 中枢神经系统（CNS）的慢性病毒疾病 以深刻的免疫调节为特征 血液和脊柱中病毒反应性CD8+ T细胞的频率 体液。 基于CD8 T细胞上表面分子的表达和 在其相对端粒长度上，看来CD11b+CD28-T细胞 和CD11b-/CD28+ T细胞可能定义CD8+ T细胞的相互子集。 CD28似乎可以识别出具有的CD8+ T细胞的幼虫 端粒长度等于来自同一个体的CD4+ T细胞， 可以刺激以区分细胞毒性或其他效应子 通过TCR/CD3复合物和CD28的适当共刺激细胞。 另一方面，CD28-/CD11b+ T细胞似乎代表 寡聚体扩展的记忆表型，可能含有病毒 特定的CD8+T细胞，并且在中缩短了端粒 与同一个人中的CD28+对应物进行比较，因此 暗示在寡聚群体中有更多的划分 扩张。 但是，对这些子集的调查已经 由于难以产生T细胞克隆的困难而阻碍。 我们有 确定的条件是常规生成两者的CD8+ T细胞克隆 功能子集，这使我们首次调查 这些子集在生化的功能差异 等级。 我们已经证明了T细胞激活和 正常个体中亚群之间的细胞因子分泌，均在 新鲜分离的PBMC和克隆水平。 我们假设这一点 CD8+/CD11b+ T细胞代表了一个预先活化的，病毒特异性的 体内人口。研究该子集在分子水平 将提供有关人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，正常免疫反应。