Origin and control of self-reactive TCRs

自反应TCR的起源和控制

• 批准号: 8460008
• 负责人: Eric S Huseby
• 金额: $ 34.53万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460008
• 关键词: Address; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Chromogranin A; DNA Sequence Rearrangement; Data; Defect; Dependence; Event; Failure; Frequencies; Genes; Goals; Immune; Inbred NOD Mice; Individual; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Lead; Ligands; Lymphocyte Subset; MHC binding peptide; Mature T-Lymphocyte; Modeling; Modification; Molecular; Molecular Conformation; Mus; Pattern; Peptide/MHC Complex; Peptides; Phenotype; Process; Proteins; Regulation; Role; Self-control as a personality trait; Shapes; Specificity; Staging; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymocyte Selection; Tissues; base; central tolerance; cross reactivity; islet; novel; peripheral tolerance; research study

DESCRIPTION (provided by applicant): The overarching goals of this project are to elucidate the roles of TCR??? pairing and thymic selection in creating the T cell repertoire specific for foreign antigens, and to identify how failures in this process lead to Type-1 Diabetes. We have identified TCRs with a variety of peptide-MHC (pMHC) reactivity patterns, some of which are self-tolerant and pMHC specific while others are overtly self-reactive and pMHC cross-reactive. Our preliminary studies show that this spectrum of TCR reactivity patterns occurs because particular TCR V gene residues can bind pMHC using a variety of different binding modes. The first set of experiments of this proposal will uncover how TCRs are created with different pMHC binding modes, and determine if a subset of pMHC binding modes are intrinsically self-reactive. The second set of experiments in this proposal will test the model that central tolerance functions to limit mature T cells from expressing TCRs with an enhanced pMHC cross-reactive phenotype, and that self-reactive T cells that also have enhanced pMHC cross-reactivity are the subset of lymphocytes which trigger the autoimmune cascade leading to Type-1 Diabetes. We will determine whether defects in negative selection in autoimmune susceptible NOD mice allow a subset of self-reactive T cells to develop that express TCRs with enhanced pMHC cross-reactivity. We predict cross-reactive T cells are the most difficult T cell subset to control throuh peripheral tolerance mechanism, and it is these T cells which become activated and trigger the autoimmune cascade causing T1D. These experiments proposal will identify molecular mechanisms that control the specificity of TCRs, and identify how defects in immune regulation allow self-reactive T cells to trigger Type 1 Diabetes.

描述（由申请人提供）：该项目的总体目标是阐明 TCR 的作用？？？配对和胸腺选择创建针对外来抗原的 T 细胞库，并确定此过程中的失败如何导致 1 型糖尿病。我们已经鉴定出具有多种肽-MHC (pMHC) 反应模式的 TCR，其中一些具有自身耐受性和 pMHC 特异性，而另一些则具有明显的自身反应性和 pMHC 交叉反应性。我们的初步研究表明，出现这种 TCR 反应模式是因为特定的 TCR V 基因残基可以使用多种不同的结合模式结合 pMHC。该提案的第一组实验将揭示如何使用不同的 pMHC 结合模式创建 TCR，并确定 pMHC 结合模式的子集是否具有本质上的自反应性。该提案中的第二组实验将测试以下模型：中枢耐受功能限制成熟 T 细胞表达具有增强 pMHC 交叉反应表型的 TCR，并且具有增强 pMHC 交叉反应性的自身反应性 T 细胞是触发自身免疫级联反应导致 1 型糖尿病的淋巴细胞亚群。我们将确定自身免疫易感性 NOD 小鼠的阴性选择缺陷是否会导致一部分自身反应性 T 细胞发育，从而表达具有增强的 pMHC 交叉反应性的 TCR。我们预测交叉反应性 T 细胞是最难通过外周耐受机制控制的 T 细胞亚群，正是这些 T 细胞被激活并触发自身免疫级联反应，导致 T1D。这些实验提案将确定控制 TCR 特异性的分子机制，并确定免疫调节缺陷如何导致自身反应性 T 细胞引发 1 型糖尿病。