CD8 T Cell Recognition of MHC Class I

描述(申请人提供)：免疫系统提供主要的宿主防御细胞内的病原体和肿瘤。在胸腺的阳性选择过程中，CD8 T淋巴细胞获得了特异性地区分感染和恶性细胞与正常细胞的能力。CD8T细胞能够与外源抗原肽结合的自身MHC发生特异而强烈的反应，同时对自身多肽结合的自身MHC保持耐受性。大多数研究一致认为，正选择涉及TCR对多肽/MHC复合体的组合识别，但驱动正选择的特定多肽/MHC配体的性质仍然难以捉摸，也存在争议。肽在T细胞谱系阳性选择中的作用是几个悬而未决的问题的核心。如果在发育过程中涉及到多肽，它对外周CD8 T细胞激活的多肽特异性有何影响？此外，所涉及的多肽的性质以及它们与抗原肽的关系仍然存在争议。此外，单一多肽/MHC在多大程度上能够驱动正选择仍然存在很大争议。例如，一个仍然存在激烈争论的问题是，与任何一个自体多肽的特定相互作用是否选择了一组有限的或多样化的TCR。尽管之前的几个优雅的报告已经解决了这些问题，特别是使用OVAp/Kb和VSVp/Kb系统，但由于自体多肽库的巨大规模，使用器官培养的体外研究结果很难扩展到体内模型。因此，确定驱动正选择的多肽/MHC复合体与所选择的谱系之间的关系仍然是一个挑战。然而，我们最近开发出了仅表达OVAp/Kb复合体或VSVp/Kb复合体的独特小鼠品系。使用严格的克隆性T细胞方法，结合分离KB自身多肽和广泛的多肽特异性测试，本申请中提出的实验将确定多肽在CD8T细胞选择中的作用。这些研究将解决有关CD8 T细胞发育的悬而未决的问题。我们将确定对单一多肽/MHCI复合体的选择如何影响CD8T细胞库的大小和多样性。这一分析将使我们能够确定正选择是否确实是多肽专一性的。我们将建立选择多肽和同源多肽之间的关系，并确定结构相似性对CD8T细胞库的发展和功能的影响。

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.