PEPTIDES/MHC I COMPLEXES AND CD8+ T CELLS

在这项正在进行的小鼠CD8 T淋巴细胞的研究中，我们的重点将从研究它们的离体，作为长期培养的克隆，转移到研究它们在小鼠的自然栖息地。在此过程中，我们将重点开发免疫原和免疫策略，刺激幼稚CD8细胞成为效应细胞，主要是细胞毒性T淋巴细胞（CTL）。为了开发这种有可能在大量人群中应用的“CD8疫苗”，我们的重点将放在含有蛋白质或大蛋白质片段的免疫原上，这些蛋白质或大蛋白质片段最终可以进入抗原提呈细胞的适当抗原加工途径。DNA疫苗目前有望用于这一目的。Heath休克融合蛋白最近成为可能的备选方案。一个主要目标将是对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，可用于已充分研究的CD8 T细胞克隆的抗原特异性受体的有效八肽激动剂（2C）。从表达该受体（2C TCR）的转基因小鼠开始，我们将分析其2 TCR+细胞在不同小鼠（包括转基因供体细胞的过继移植受体）中对这些免疫原的反应。其他的研究将集中在i)阐明热休克融合蛋白不寻常的免疫原性的基础，ii)开发一个肿瘤模型来跟踪CD8 T细胞在小鼠中的迁移和分布，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，有些细胞有CD8共受体分子，有些没有。

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.