The Relationship between TCR Revision and Follicular Helper T Cells

描述（由申请人提供）：成熟的外周CD4+ T细胞在Vb5转基因（Tg）小鼠中的自我耐受性通过两种途径发生，缺失和T细胞受体（TCR）修订。这两个过程都是由小鼠乳腺肿瘤病毒（Mtv）编码的外周表达的自身抗原慢性接触所驱动的8。树突状细胞对Mtv-8表达的识别使CD4+Vb5+ T细胞失能，导致其缺失，并伴随外周血CD4:CD8比值的倒置。长期识别B细胞上Mtv-8的T细胞进入生发中心并进行TCR修正。在TCR修饰过程中，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，并对内源性TCR Vb基因进行重排。外周T细胞中Rag的缺失阻断了TCR的修正。改良后的T细胞是Vb5-并且不能识别Mtv-8，但表达多种TCRb曲目，并且自身mhc受限且具有功能。这项探索性资助的目标是将修改T细胞的群体置于已知功能的定义T细胞亚群的背景下。我们之前在TCR修正过程中对T细胞的表征暗示了与滤泡辅助性T细胞室的表型重叠。通过这项试点资助，我们将确定修饰T细胞频率与生发中心B和T细胞之间的关系，并确定修饰T细胞是否具有滤泡辅助性T细胞的表型和功能特征。这些实验将有助于将TCR修改置于T细胞免疫学的更大框架内，并将探索TCR修改如何影响适应性免疫反应的B细胞臂。

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.