PEPTIDES/MHC I COMPLEXES AND CD8+ T CELLS

肽/MHC I 复合物和 CD8 T 细胞

• 批准号: 6172323
• 负责人: HERMAN N EISEN
• 金额: $ 22.49万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-07 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172323
• 关键词: CD8 molecule; MHC class I antigen; T cell receptor; antigen presentation; biological models; chimeric proteins; cytotoxic T lymphocyte; genetically modified animals; green fluorescent proteins; laboratory mouse; model design /development; neoplasm /cancer; neoplasm /cancer immunotherapy; peptides; receptor binding; stress proteins; tissue /cell culture; vector vaccine

In this ongoing study of murine CD8 T lymphocytes our emphasis will shift from studying them ex vivo, as clones in long-term culture, to studying them in mice, their natural habitat. In making the transition, we will focus on developing immunogens and immunization strategies that stimulate naive CD8 cells to become effector cells, primarily cytotoxic T lymphocytes (CTL). To develop such "CD8 vaccines", having the possibilities for application in large human populations, our emphasis will be on immunogens that contain proteins or large protein fragments that can end up in the proper antigen-processing pathway of antigen- presenting cells. DNA vaccines are currently promising for this purpose. Heath shock fusion proteins have recently emerged as possible alternative candidates. A major aim will be to carry out comparative studies of DNA vaccines and heat shock fusion proteins, both having (or encoding) the same polypeptide precursor of a potent octapeptide agonist for the antigen-specific receptor of a well studied CD8 T cell clone (2C). Starting with transgenic mice expressing this receptor (2C TCR), we will analyze the response of their 2 TCR+ cells to these immunogens in various mice, including adoptive transfer recipients of the cells from transgenic donors. Other studies will concentrate on i) elucidating the basis for the unusual immunogenic properties of heat shock fusion proteins, ii) developing a tumor model for tracking the mobility and distribution in mice of CD8 T cells whose TCR recognizes peptide-MHC complexes on the tumor cells, and iii) comparing TCR affinity on live 2C cells, some having and some not having CD8 co-receptor molecules.

在这项正在进行的小鼠 CD8 T 淋巴细胞研究中，我们的重点将从离体研究它们（作为长期培养中的克隆）转移到在小鼠（它们的自然栖息地）中研究它们。在转型过程中，我们将重点开发免疫原和免疫策略，刺激初始 CD8 细胞成为效应细胞，主要是细胞毒性 T 淋巴细胞 (CTL)。为了开发这种具有在大量人群中应用的可能性的“CD8疫苗”，我们的重点将是含有蛋白质或大蛋白质片段的免疫原，这些蛋白质或大蛋白质片段可以最终进入抗原呈递细胞的正确抗原加工途径。 DNA 疫苗目前有望用于此目的。希思休克融合蛋白最近已成为可能的替代候选者。主要目标是对 DNA 疫苗和热休克融合蛋白进行比较研究，两者都具有（或编码）相同的多肽前体，该前体是有效八肽激动剂，用于经过充分研究的 CD8 T 细胞克隆的抗原特异性受体 (2C)。从表达该受体 (2C TCR) 的转基因小鼠开始，我们将分析各种小鼠中 2 个 TCR+ 细胞对这些免疫原的反应，包括来自转基因供体的细胞的过继转移受体。其他研究将集中于 i) 阐明热休克融合蛋白不寻常的免疫原性特性的基础，ii) 开发一种肿瘤模型，用于追踪小鼠体内 CD8 T 细胞的迁移性和分布，这些细胞的 TCR 识别肿瘤细胞上的肽-MHC 复合物，以及 iii) 比较 TCR 对活 2C 细胞的亲和力，其中一些细胞具有和一些不具有 CD8 共受体分子。