The Relationship between TCR Revision and Follicular Helper T Cells

描述（由申请方提供）：Vb 5转基因（Tg）小鼠中成熟外周CD 4 + T细胞的自身耐受通过两种途径发生，即缺失和T细胞受体（TCR）修正。这两个过程都是由小鼠乳腺肿瘤病毒（Mtv）8编码的外周表达的自身抗原的慢性遭遇驱动的。树突状细胞表达的Mtv-8的识别使CD 4 + Vb 5 + T细胞无反应性，并导致其缺失和伴随的外周CD 4：CD 8比率的倒置。长期识别B细胞上Mtv-8的T细胞进入生殖中心并进行TCR修正。在TCR修复过程中，T细胞失去Vb 5表面表达，上调淋巴细胞特异性重组酶机制（RAG 1、RAG 2和TdT）的表达，并重排内源性TCR Vb基因。外周T细胞中Rag的缺失阻断TCR修正。修正后的T细胞是Vb 5-，不能识别Mtv-8，但表达不同的TCRb库，是自身MHC限制性和功能性的。这项探索性资助的目标是将修订的T细胞群体置于已知功能的定义的T细胞亚群的背景下。我们先前对TCR修订过程中T细胞的表征暗示了与滤泡辅助T细胞区室的表型重叠。利用该试点基金，我们将确定修正T细胞与生发中心B和T细胞的频率之间的关系，并确定修正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应答的B细胞臂。 公共卫生相关性：T细胞受体修复是诱导成熟外周T细胞自身耐受的一种手段，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T细胞占据什么样的细胞区室，它们执行什么样的功能，以及它们与什么样的其他细胞类型相互作用，将有助于我们了解T细胞受体修正过程中固有的风险，并将有助于将这种耐受途径置于不断增长的机制列表中，以帮助预防T细胞驱动的自身免疫。

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.