ANTIGEN-SPECIFIC T-CELL ACTIVATION AND GENETIC CONTROL OF IMMUNE RESPONSES

抗原特异性 T 细胞激活和免疫反应的基因控制

• 批准号: 3962927
• 负责人: J A BERZOFSKY
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3962927
• 关键词: AIDS; B lymphocyte; T lymphocyte; antiantibody; antibody specificity; antigen antibody reaction; autoimmune disorder; cell cell interaction; chromatography; clone cells; enzyme linked immunosorbent assay; genetic regulation; histocompatibility antigens; hybridomas; immune response genes; immunochemistry; immunogenetics; leukocyte activation /transformation; lymphokines; monoclonal antibody; myoglobin; radioimmunoassay; radiotracer; saltwater environment

We have studied the mechanism of T-cell activation by antigen, and the MHC-linked genetic control thereof. In contrast to antibodies, the T-cell response is dominated by a few immunodominant antigenic sites, which represent regions on which a polyclonal T-cell response is focused. We found that the immunodominance of a site can be determined both by extrinsic factors, such as the major histocompatibility (MHC) antigens of the responder, and by intrinsic factors in the antigen structure. The two immunodominant sites of myoglobin we found around residues 109 and 140 were recognized with different MHC antigens, I-Ad and I-Ed, respectively. With synthetic peptides, we narrowed these sites to 106-118 and 133-146, respectively. Both of these are amphipathic alpha helices. We examined the 23 known immunodominant sites from 12 different proteins, and found that 18 of these have a periodicity of hydrophobicity that would make them amphipathic if they fold as an alpha helix. We have developed an algorithm to search for such sequences and are using this to predict T-cell sites from AIDS and malaria proteins, for purposes of developing synthetic vaccines. Corresponding peptides are being prepared and tested. Using a biotinylated immunodominant peptide, we showed that the peptide was on the surface of the presenting cell, accessible to macromolecules such as avidin. We found that the cloned, antigen-specific, Ia-restricted, L3T4+ T cells also killed tumor but not normal presenting cells. The induction was antigen-specific, but the effector phase was not, although it was preferentially inhibited by specific cold targets. This may represent a novel type of tumor surveillance. We also found that on antigen stimulation, the T-cell clones release soluble IL-2 receptor, secrete a new lymphokine that stimulates IL-1 secretion by macrophages, and increase their expression of Fc receptors for IgD (also induced by IgD itself). We also found a novel population of L3T4+, IL-2 receptor-bearing T cells in unstimulated normal spleen cells, whose level is controlled by several genes including one mapped to chromosome 7.

我们已经研究了抗原T细胞激活的机制， MHC连接的遗传控制。 与抗体相反，T细胞 反应由一些免疫主导抗原部位主导，这些抗原部位 表示聚克隆T细胞响应集中的区域。 我们 发现位点的免疫力可以通过 外部因素，例如主要组织相容性（MHC）抗原 响应者以及抗原结构中的内在因素。 两个 我们在残基109和140周围发现的肌红蛋白的免疫主导地点是 分别具有不同的MHC抗原，I-AD和I-ED。 和 合成肽，我们将这些位点范围缩小到106-118和133-146， 分别。 这两个都是两亲α螺旋。 我们检查了 来自12种不同蛋白质的23个已知的免疫主导位点，发现 其中18个具有疏水性的周期性 两亲性如果它们折叠为Alpha螺旋。 我们已经开发了一种算法 搜索此类序列并正在使用它来预测T细胞位点 从艾滋病和疟疾蛋白中，出于开发合成的目的 疫苗。 正在制备和测试相应的肽。 使用 生物素化的免疫主导肽，我们表明肽在 呈现细胞的表面，可用于大分子（例如 avidin。 我们发现克隆的，抗原特异性的IA限制性L3T4+ T 细胞还杀死肿瘤，但不是正常的表现细胞。 诱导是 抗原特异性，但效应阶段不是，尽管它是 特定的冷目标优先抑制。 这可能代表 新型肿瘤监测类型。 我们还发现在抗原上 刺激，T细胞克隆释放可溶性IL-2受体，分泌一个新的 通过巨噬细胞刺激IL-1分泌的淋巴细胞动物，并增加 它们对IgD的FC受体的表达（也由IgD本身诱导）。 我们 还发现了新的L3T4+，IL-2受体T细胞的新种群 未刺激的正常脾细胞，其水平由几个 基因包括一个映射到7号染色体的基因。