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.

我们研究了抗原激活T细胞的机制， MHC连锁的遗传控制。 与抗体相反，T细胞 免疫应答由少数免疫显性抗原位点主导， 代表多克隆T细胞应答集中的区域。 我们 发现一个位点的免疫优势可以通过以下两种方式来确定： 外源性因素，如主要组织相容性（MHC）抗原， 应答者，以及抗原结构中的内在因素。 两 我们在残基109和140附近发现的肌红蛋白的免疫显性位点是 分别用不同的MHC抗原I-Ad和I-Ed识别。 与 合成肽，我们将这些位点缩小到106-118和133-146， 分别 这两个都是两亲性α螺旋。 我们研究 来自12种不同蛋白质的23个已知免疫显性位点， 其中18种具有周期性疏水性， 如果它们折叠成α螺旋，则是两亲的。 我们已经开发了一种算法 寻找这样的序列，并利用它来预测T细胞位点， 从艾滋病和疟疾的蛋白质中， 疫苗。 正在制备和测试相应的肽。 使用 生物素标记的免疫显性肽，我们表明该肽是在 呈递细胞的表面，可接近大分子，如 亲和素。 我们发现，克隆的抗原特异性的，Ia限制性的，L3 T4 + T 细胞也能杀死肿瘤细胞，但不能杀死正常的呈递细胞。 诱导是 抗原特异性，但效应期不是，虽然它是 优先被特定的冷目标抑制。 这可能代表了一种 新型肿瘤监测。 我们还发现在抗原上 刺激后，T细胞克隆释放可溶性IL-2受体，分泌新的 刺激巨噬细胞分泌IL-1的淋巴因子， 它们表达IgD的Fc受体（也由IgD本身诱导）。 我们 还发现了一个新的L3 T4+，IL-2受体携带T细胞的群体， 未受刺激的正常脾细胞，其水平由几个 包括一个定位在7号染色体上的基因。