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淋巴细胞识别有限数量的抗原位点， 给定抗原蛋白。 我们发现， 对一个免疫显性位点的反应 在高反应者和低反应者之间，即使低反应者 响应者对其他站点的响应几乎和 响应者。 除了与主要组织相容性 (MHC)分子，我们发现，抗原是由模式 T细胞识别的片段也决定了 哪些网站可以看 天然加工的产品 蛋白质似乎比合成肽大， 这些结构阻碍与某些MHC分子的结合或与 T细胞受体 除了MHC结合和抗原加工外， 免疫优势的第三个因素是免疫球蛋白的内在结构。 抗原位点 我们以前已经证明，两亲螺旋 有很高的机会成为免疫显性，并已制定了一个 在蛋白质序列中定位这种结构的计算机程序。 我们前瞻性地预测了疟疾环子孢子中 蛋白质，并发现，四个最广泛认可的网站，在一个 西非流行区的所有预测。 同样我们 从艾滋病毒（艾滋病病毒）中鉴定出两个辅助性T细胞位点 信封，并表明，免疫与这些elevents增强 当注射到 猴子 这些位点也被人类T细胞识别， 已经用重组牛痘免疫的志愿者 表达HIV包膜的病毒。 在老鼠身上，我们已经发现 包膜蛋白中的其他免疫显性位点，包括 一个非常大的模型，在这个模型中， 识别不同的重叠区域。 此外，由于细胞毒性T 淋巴细胞（CTL）可能在防御AlDS中起关键作用， 我们使用重组牛痘病毒和转染子 表达HIV包膜基因以诱导针对HIV包膜基因的特异性CTL， 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，在这方面， 我们观察到这些地点非常有限。 这些结果可能 希望能为艾滋病疫苗的设计做出贡献。