PEPTIDES/MHC I COMPLEXES AND CD8+ T CELLS

在这项正在进行的小鼠CD 8 T淋巴细胞的研究中，我们的重点将从体外研究它们（作为长期培养的克隆）转移到在小鼠中研究它们（它们的自然栖息地）。在过渡过程中，我们将专注于开发免疫原和免疫策略，刺激幼稚CD 8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人群中应用的可能性的“CD 8疫苗”，我们的重点将是含有蛋白质或大蛋白片段的免疫原，所述蛋白质或大蛋白片段可以在抗原呈递细胞的适当抗原加工途径中结束。DNA疫苗目前有望用于这一目的。最近出现了健康休克融合蛋白作为可能的替代候选物。一个主要的目的是进行DNA疫苗和热休克融合蛋白的比较研究，两者都具有（或编码）有效的八肽激动剂的相同多肽前体，所述八肽激动剂用于充分研究的CD 8 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，我们将分析其2 TCR+细胞对各种小鼠中这些免疫原的应答，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的不寻常免疫原性性质的基础，ii）开发用于跟踪小鼠中CD 8 T细胞的移动性和分布的肿瘤模型，所述CD 8 T细胞的TCR识别肿瘤细胞上的肽-MHC复合物，以及iii）比较活2C细胞上的TCR亲和力，一些具有和一些不具有CD 8共受体分子。

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.