CD8 T Cell Recognition of MHC Class I

CD8 T 细胞对 MHC I 类的识别

• 批准号: 7144585
• 负责人: JANET M CONNOLLY
• 金额: $ 38.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144585
• 关键词: CD8 molecule; MHC class I antigen; autoantigens; autoimmunity; cytotoxic T lymphocyte; genetically modified animals; laboratory mouse; leukocyte activation /transformation; lymphopoiesis; thymus; tissue /cell culture; tumor antigens; virus antigen

DESCRIPTION (provided by applicant): The immune system provides the major host defense against intracellular pathogens and tumors. CD8 T lymphocytes acquire the ability to specifically discriminate infected and malignant cells from normal cells during positive selection in the thymus. CD8 T cells emerge with the ability to specifically and vigorously react with self MHC to which a foreign antigenic peptide is bound, yet remain tolerant to self MHC bound by self peptides. The majority of studies agree that positive selection involves combinatorial recognition by TCR of a peptide/MHC complex yet the nature of the specific peptide/MHC ligand that drives positive selection remains elusive and controversial. The role of peptide in positive selection of the T cell repertoire is at the heart of several unresolved issues. If peptide is involved during development, how does it impact on the peptide specificity of peripheral CD8 T cell activation? Furthermore, the nature of the peptides involved and their relationship to the antigenic peptides remains a matter of controversy. In addition, the extent to which a single peptide/MHC can drive positive selection is still highly controversial. For example, an issue that remains hotly debated is whether specific interaction with any one self peptide selects a limited or diverse set of TCRs. Although several elegant previous reports have addressed these questions, in particular using the OVAp/Kb and VSVp/Kb systems, it has been difficult to extend in vitro findings using organ culture to in vivo models because of the enormity of the pool of self peptides. Thus, defining the relationship between the peptide/MHC complexes that drive positive selection and the selected repertoire remains a challenge. However we have recently developed unique mouse strains that express only the OVAp/Kb complex or the VSVp/Kb complex. Using rigorous clonal T cell approaches coupled with isolation of Kb self peptides and extensive tests of peptide specificity, experiments proposed in this application will define the role of peptide in CD8 T cell selection. These studies will address unresolved questions regarding CD8 T cell development. We will determine how selection on a single peptide/MHCI complex influences the size and diversity of the CD8 T cell repertoire. This analysis will allow us to determine if positive selection is indeed peptide specific. We will establish the relationship between the selecting and cognate peptides and we will determine the impact of structural similarity on the development and function of the CD8 T cell repertoire.

描述（由申请人提供）：免疫系统提供了针对细胞内病原体和肿瘤的主要宿主防御。CD 8 T淋巴细胞在胸腺中的阳性选择过程中获得特异性区分感染和恶性细胞与正常细胞的能力。CD 8 T细胞具有特异性和强烈地与结合有外源抗原肽的自身MHC反应的能力，但仍对自身肽结合的自身MHC保持耐受。大多数研究认为，正选择涉及TCR对肽/MHC复合物的组合识别，但驱动正选择的特定肽/MHC配体的性质仍然难以捉摸且有争议。肽在T细胞库的阳性选择中的作用是几个未解决问题的核心。如果肽参与发育过程，它如何影响外周CD 8 T细胞活化的肽特异性？此外，所涉及的肽的性质及其与抗原肽的关系仍然是一个有争议的问题。此外，单个肽/MHC可以在多大程度上驱动正选择仍然存在很大争议。例如，一个仍然激烈争论的问题是，与任何一种自身肽的特异性相互作用是否选择了有限或多样的TCR组。尽管先前的几篇精彩报道已经解决了这些问题，特别是使用OVAp/Kb和VSVp/Kb系统，但由于自身肽库的重复性，很难将使用器官培养的体外发现扩展到体内模型。因此，确定驱动阳性选择的肽/MHC复合物与所选库之间的关系仍然是一个挑战。然而，我们最近开发了仅表达OVAp/Kb复合物或VSVp/Kb复合物的独特小鼠品系。使用严格的克隆T细胞方法，结合Kb自身肽的分离和肽特异性的广泛测试，本申请中提出的实验将定义肽在CD 8 T细胞选择中的作用。这些研究将解决有关CD 8 T细胞发育的未解决问题。我们将确定如何选择一个单一的肽/MHCI复合物的影响的大小和多样性的CD 8 T细胞库。该分析将允许我们确定阳性选择是否确实是肽特异性的。我们将建立选择肽和同源肽之间的关系，并确定结构相似性对CD 8 T细胞库的发育和功能的影响。