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: 3916273
• 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/3916273
• 关键词: AIDS; Plasmodium; T lymphocyte; antibody receptor; antigen presentation; antigens; binding proteins; cell cell interaction; human immunodeficiency virus 1; immune response genes; immunogenetics; immunoglobulin idiotypes; laboratory mouse; leukocyte activation /transformation; major histocompatibility complex; malaria; malaria vaccines; myoglobin; protein sequence; synthetic peptide; vaccinia virus; viral vaccines; virus envelope

T lymphocytes recognize a limited number of antigenic sites on any given antigenic protein. We find that the presence or absence of a response to one immunodominant site can make the difference between a high responder and a low responder, even though low responders respond to other sites almost as well as high responders. Besides interaction with major histocompatibility (MHC) molecules, we find that the mode by which the antigen is processed into fragments for T-cell recognition also determines which sites are seen. The products of natural processing of the protein appear to be larger than the synthetic peptides and contain structures which hinder binding to certain MHC molecules or to the T-cell receptor. Besides MHC binding and antigen processing, a third factor in immunodominance is the intrinsic structure of the antigenic site. We have previously shown that amphipathic helices have a high chance of being immunodominant, and have developed a computer program to locate such structures in protein sequences. We prospectively predicted sites in the malaria circumsporozoite protein and found that the four most widely recognized sites in an endemic area of West Africa were all predicted. Similarly, we identified two helper T-cell sites from the HIV (AlDS virus) envelope, and showed that immunization with these elicits enhanced antibody responses to the whole envelope when injected into monkeys. These sites are also recognized by human T cells from volunteers who have been immunized with a recombinant vaccinia virus expressing the HlV envelope. In mice, we have now identified other immunodominant sites in the envelope protein, including a very large one within which different MHC types of mice each recognize different overlapping regions. Also, since cytotoxic T lymphocytes (CTL) may play a critical role in defense against AlDS, we have used a recombinant vaccinia virus and transfectants expressing the HIV envelope gene to induce specific CTL against the HIV envelope. Using synthetic peptides, we were able to identify the first known CTL recognition site in the AIDS virus. However, we observed that such sites are very limited. These results may hopefully contribute_to the design of a vaccine for AIDS.

T淋巴细胞识别出任何有限的抗原位点 给定抗原蛋白。 我们发现存在或不存在 对一个免疫主导地点的反应可以使您有所作为 在高响应者和低响应者之间，即使 响应者对其他站点的反应几乎和高 响应者。 除了与主要的组织兼容性相互作用 （MHC）分子，我们发现抗原是 处理成T细胞识别的片段也决定了 看到哪些站点。 自然处理的产品 蛋白质似乎比合成肽大，并且包含 阻碍与某些MHC分子或与该结构结合的结构 T细胞受体。 除了MHC结合和抗原处理外， 免疫主持的第三个因素是 抗原部位。 我们以前已经证明了两亲螺旋 有很大的免疫降低机会，并发展了 计算机程序以蛋白质序列定位此类结构。 我们前瞻性地预测了疟疾割孢子虫的地点 蛋白质，发现四个最广泛认可的位点 预测西非的地方性地区。 同样，我们 从HIV（ALDS病毒）鉴定出两个辅助T细胞位点 信封，并表明通过这些引起的免疫增强了 注入到整个信封的抗体反应 猴子。 这些位点也被人类T细胞识别 用重组疫苗接种的志愿者 表达HLV信封的病毒。 在老鼠中，我们现在已经确定 包膜蛋白中的其他免疫降低部位，包括A 非常大的小鼠中不同的MHC类型 识别不同的重叠区域。 另外，由于细胞毒性T 淋巴细胞（CTL）可能在防御ALDS中起关键作用， 我们使用了重组疫苗病毒和转染剂 表达HIV信封基因以诱导特定的CTL针对 艾滋病毒信封。 使用合成肽，我们能够识别 艾滋病病毒中第一个已知的CTL识别位点。 然而， 我们观察到这样的站点非常有限。 这些结果可能 希望为艾滋病的疫苗设计贡献。