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，外周CD4+ T细胞的自耐耐受性通过两种途径，缺失和T细胞受体（TCR）修订。这两个过程均由由小鼠乳腺肿瘤病毒（MTV）编码的外周表达的自我抗原（MTV）8的慢性接触驱动。对树突状细胞表达的MTV-8的识别会导致CD4+ VB5+ T细胞的厌食症，并导致其缺失的结果，并导致其缺失及其对同伴的逆转倒置CD4：CD8比率。慢性识别B细胞上MTV-8的T细胞进入生发中心并进行TCR修订。在TCR修订过程中，T细胞失去VB5表面表达，上调淋巴细胞特异性重组酶机械的表达（RAG1，RAG2和TDT），以及重新排列的内源性TCR VB基因。外围T细胞中抹布的删除会阻止TCR修订。修订后T细胞为VB5，无法识别MTV-8，但表达了多样化的TCRB曲目，并且是自我MHC的限制和功能。该探索性授予的目的是在已知功能的定义T细胞亚群中放置修订T细胞的种群。在TCR修订过程中，我们先前对T细胞的表征暗示了与卵泡辅助T细胞室的表型重叠。使用此试点赠款，我们将确定修饰T细胞和生发中心B和T细胞的频率之间的关系，并确定修订的T细胞是否具有卵泡辅助T细胞的表型和功能特征。这些实验将有助于将TCR修订放置在更大的T细胞免疫学框架内，并将探讨TCR修订如何影响适应性免疫反应的B细胞组。 公共卫生相关性：T细胞受体修订是诱导成熟外周T细胞中自耐力的一种手段，并导致通过基因重组年龄依赖于年龄的表达。了解哪些细胞室修改T细胞占据的占据哪些功能以及与哪些其他细胞类型相互作用将有助于我们了解T细胞受体修订过程中固有哪些风险，并将有助于将这种耐受性途径放置在不断增长的机制列表中，这些机制有助于防止T细胞驱动自身免疫性。