The Relationship between TCR Revision and Follicular Helper T Cells

TCR 修正与滤泡辅助 T 细胞的关系

• 批准号: 8231750
• 负责人: Pamela J Fink
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231750
• 关键词: Adoptive Transfer; Affinity; Antigen Receptors; Autoantigens; Autoimmunity; B-Lymphocytes; BLR1 gene; Bacterial Infections; Bone Marrow; CD 200; CD28 gene; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; Cell Communication; Cell surface; Cells; Characteristics; Chimera organism; Chronic; Communication; Complex; Dancing; Dendritic Cells; Endogenous Retroviruses; Erythrocytes; Frequencies; Genes; Genetic Recombination; Genetic Transcription; Goals; Grant; Helper-Inducer T-Lymphocyte; Immune response; Immunoglobulin Class Switching; Immunology; Interleukin-10; Interleukin-17; Interleukin-4; Lymphocyte; Mediating; Mesentery; Modeling; Mouse Mammary Tumor Virus; Mus; Pathway interactions; Pattern; Peripheral; Phenotype; Population; Process; Proteins; Relative (related person); Reporter; Risk; STAT3 gene; Self Tolerance; Sheep; Signal Transduction; Signaling Molecule; Spleen; Structure of aggregated lymphoid follicle of small intestine; Structure of germinal center of lymph node; Superantigens; Surface; Surface Antigens; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Transgenic Mice; Transgenic Organisms; Ursidae Family; Work; age related; arm; cell type; cytokine; lymph nodes; mammary tumor virus; migration; prevent; programs; recombinase; research study; transcription factor

DESCRIPTION (provided by applicant): Self-tolerance of mature, peripheral CD4+ T cells in Vb5 transgenic (Tg) mice occurs through two pathways, deletion and T cell receptor (TCR) revision. Both processes are driven by chronic encounter with a peripherally expressed self-antigen encoded by mouse mammary tumor virus (Mtv) 8. Recognition of Mtv-8 expressed by dendritic cells renders CD4+Vb5+ T cells anergic and results in their deletion and the concomitant inversion of the peripheral CD4:CD8 ratio. T cells that chronically recognize Mtv-8 on B cells instead enter the germinal center and undergo TCR revision. During the process of TCR revision, T cells lose Vb5 surface expression, upregulate expression of the lymphocyte-specific recombinase machinery (RAG1, RAG2, and TdT), and rearrange endogenous TCR Vb genes. Deletion of Rag in peripheral T cells blocks TCR revision. Post revision T cells are Vb5- and fail to recognize Mtv-8, yet express a diverse TCRb repertoire and are self-MHC restricted and functional. The goal of this exploratory grant is to place the population of revising T cells in the context of a defined T cell subpopulation of known function. Our previous characterization of T cells in the process of TCR revision hint at a phenotypic overlap with the follicular helper T cell compartment. With this pilot grant, we will determine the relationship between the frequencies of revising T cells and germinal center B and T cells, and determine whether revising T cells bear the phenotypic and functional characteristics of follicular helper T cells. These experiments will help place TCR revision within the larger framework of T cell immunology, and will explore how TCR revision may impact the B cell arm of the adaptive immune response. PUBLIC HEALTH RELEVANCE: T cell receptor revision is a means for inducing self tolerance in mature peripheral T cells, and results in the age-dependent expression of an extrathymically-generated antigen receptor repertoire through gene recombination. Understanding what cell compartment revising T cells occupy, what functions they perform, and what other cell types they interact with will help us understand what risks are inherent in the process of T cell receptor revision and will help place this tolerance pathway within the growing list of mechanisms in place that serve to help prevent T cell driven autoimmunity.

描述（由申请人提供）：Vb5 转基因（Tg）小鼠中成熟的外周 CD4+ T 细胞的自我耐受通过两种途径发生：缺失和 T 细胞受体（TCR）修正。这两个过程都是由与小鼠乳腺肿瘤病毒 (Mtv) 8 编码的外周表达的自身抗原的长期接触驱动的。树突状细胞表达的 Mtv-8 的识别使 CD4+Vb5+ T 细胞无反应，导致其缺失和伴随的倒位。外周 CD4:CD8 比率。相反，长期识别 B 细胞上 Mtv-8 的 T 细胞会进入生发中心并进行 TCR 修正。在 TCR 修正过程中，T 细胞失去 Vb5 表面表达，上调淋巴细胞特异性重组酶机制（RAG1、RAG2 和 TdT）的表达，并重新排列内源 TCR Vb 基因。外周 T 细胞中 Rag 的缺失会阻止 TCR 修正。修订后的 T 细胞为 Vb5-，无法识别 Mtv-8，但表达多种 TCRb 库，并且具有自我 MHC 限制和功能。这项探索性资助的目标是将修正 T 细胞群置于已知功能的已定义 T 细胞亚群的背景下。我们之前对 TCR 修正过程中 T 细胞的表征暗示了与滤泡辅助 T 细胞区室的表型重叠。通过这笔试点资助，我们将确定修改 T 细胞与生发中心 B 和 T 细胞的频率之间的关系，并确定修改 T 细胞是否具有滤泡辅助 T 细胞的表型和功能特征。这些实验将有助于将 TCR 修订置于 T 细胞免疫学的更大框架内，并将探索 TCR 修订如何影响适应性免疫反应的 B 细胞臂。 公共卫生相关性：T 细胞受体修正是诱导成熟外周 T 细胞自我耐受的一种方法，并通过基因重组导致胸腺外产生的抗原受体库的年龄依赖性表达。了解修改 T 细胞占据的细胞区室、它们执行的功能以及它们与哪些其他细胞类型相互作用，将有助于我们了解 T 细胞受体修改过程中固有的风险，并将有助于将这种耐受途径纳入不断增长的列表中。有助于预防 T 细胞驱动的自身免疫的机制。