CD8 T Cell Recognition of MHC Class I

描述（由申请人提供）：免疫系统提供宿主对细胞内病原体和肿瘤的主要防御。在胸腺的阳性选择过程中，CD8 T淋巴细胞获得特异性区分感染细胞和恶性细胞与正常细胞的能力。CD8 T细胞具有特异性和强烈地与外源抗原肽结合的自身MHC反应的能力，但仍能耐受由自身肽结合的自身MHC。大多数研究都认为，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存在争议。肽在T细胞库阳性选择中的作用是几个尚未解决的问题的核心。如果在发育过程中涉及肽，它如何影响外周CD8 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在多大程度上可以驱动阳性选择仍然存在很大争议。例如，一个仍然争论激烈的问题是，与任何一种自肽的特定相互作用是否选择了一组有限或多样化的tcr。尽管之前的一些报告已经解决了这些问题，特别是使用OVAp/Kb和VSVp/Kb系统，但由于自身肽库的巨大，很难将体外器官培养的研究结果扩展到体内模型。因此，确定驱动阳性选择的肽/MHC复合物与选择曲目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复合体或VSVp/Kb复合体的独特小鼠品系。采用严格的克隆T细胞方法，结合分离Kb自身肽和广泛的肽特异性测试，本应用程序中提出的实验将确定肽在CD8 T细胞选择中的作用。这些研究将解决有关CD8 T细胞发育的尚未解决的问题。我们将确定单个肽/MHCI复合物的选择如何影响CD8 T细胞库的大小和多样性。这种分析将使我们确定阳性选择是否确实是肽特异性的。我们将建立选择和同源肽之间的关系，我们将确定结构相似性对CD8 T细胞库的发育和功能的影响。

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.