Transcriptional control of chemokine receptors and naive T cell trafficking

描述（由申请人提供）：T细胞运输是适应性免疫的基本组成部分，无论是在有效清除外来病原体还是限制自身免疫方面。初始T细胞迁移限于通过血管和淋巴管互连的一系列外周次级淋巴器官，而活化的效应T细胞可以逃离该循环回路并进入外周组织。为了实现这些不同的迁移模式，初始T细胞和效应T细胞分别通过稳态和炎性趋化因子受体（CR）对不同的趋化因子梯度作出响应。当初始T细胞与活化的抗原呈递细胞相互作用时，T细胞在免疫应答期间获得炎性CR，然而，参与这种受体调节的T细胞内在分子机制目前尚不清楚。在这方面，初步的证据表明，转录因子，Kr <$ppel样因子2（Klf 2），可能在控制CR基因表达中起着至关重要的作用。缺乏Klf 2的初始T细胞表达炎性CR并获得新的运输模式，包括外周非次级淋巴器官中的初始T细胞分布。此外，幼稚T细胞的子集似乎下调稳态CR。因此，我们假设Klf 2调节CR基因的转录，这是维持初始T细胞处于稳态循环模式和限制T细胞介导的免疫应答所必需的。该中心假设将通过实现三个独立的目标来解决：（目标1）鉴定抑制炎性CR并诱导稳态CR基因转录的Klf 2依赖性机制;（目标2）使用Klf 2缺陷型T细胞评估这些CR的功能状态并确定哪些CR负责体内异常幼稚Klf 2缺陷型T细胞运输，以及;（目的3）确定无限制的初始T细胞运输如何在细胞内在水平（无反应性对完整的T细胞效应子功能）以及在宿主水平（免疫受损宿主对有效的病原体清除对自身免疫）影响细胞免疫。这些研究应提供重要的信息，在幼稚T细胞的CR基因调控，非典型CR表达的影响T细胞迁移和幼稚T细胞贩运到外周组织的免疫后果。这项研究对于广泛的生物学过程（如CR调节）以及临床条件（如病原体清除和T细胞介导的疾病，如自身免疫性心肌炎）都具有重要意义。公共卫生相关性：T淋巴细胞介导免疫应答，包括期望的（如清除致病病毒）和不期望的（如攻击自身免疫性疾病中的自身组织）。该项目的目标是确定T细胞如何迁移到各种组织以执行这些不同的功能，并找出当这种迁移过程发生故障时会发生什么。这项研究在病原体清除和自身免疫方面都具有重要意义，具有潜在的治疗应用。

DESCRIPTION (provided by applicant): T cell trafficking is a fundamental component of adaptive immunity, both in terms of effectively clearing foreign pathogens as well as limiting autoimmunity. Naive T cell migration is limited to a series of peripheral secondary lymphoid organs interconnected via blood and lymphatic vessels whereas activated effector T cells can escape this circulatory loop and enter peripheral tissues. To achieve these distinct migration patterns, naive and effector T cells respond to diverse chemokine gradients via homeostatic and inflammatory chemokine receptors (CRs), respectively. T cells acquire inflammatory CRs during an immune response when naive T cells interact with activated antigen presenting cells, however, the T cell-intrinsic molecular mechanisms involved in this receptor regulation are currently unknown. In this regard, preliminary evidence indicates that the transcription factor, Kr¿ppel-like factor 2 (Klf2), may play a crucial role in controlling CR gene expression. Naive T cells lacking Klf2 express inflammatory CRs and acquire novel trafficking patterns, including naive T cell distribution in peripheral non-secondary lymphoid organs. In addition, a subset of naive T cells appear to downregulate homeostatic CRs. Therefore, we hypothesize that Klf2 regulates transcription of CR genes, which is necessary for maintaining naive T cells in a homeostatic circulatory pattern and restricting T cell-mediated immune responses. This central hypothesis will be addressed by achieving three independent goals: (Aim 1) identifying Klf2-dependent mechanisms that repress inflammatory CRs and induce homeostatic CR gene transcription; (Aim 2) assessing the functional status of these CRs using Klf2-deficient T cells and determining which CRs are responsible for aberrant naive Klf2-deficient T cell trafficking in vivo, and; (Aim 3) establishing how unrestrained naive T cell trafficking affects cellular immunity at the cell-intrinsic level (anergy versus intact T cell effector functions) as well as at a host level (immunocompromised host versus effective pathogen clearance versus autoimmunity). These studies should provide important information concerning CR gene regulation in naive T cells, the affect atypical CR expression has on T cell migration and the immunological consequences of naive T cell trafficking into peripheral tissues. This research has important implications both with regards to broad biological processes such as CR regulation as well as clinical conditions such as pathogen clearance and T cell-mediated diseases like autoimmune myocarditis. Public Health Relevance: T lymphocytes mediate immune responses, both desired (such as clearance of disease-causing viruses) and undesired (such as attacking self-tissues in autoimmune diseases). The goal of this project is to determine how T cells migrate to various tissues to carry out these diverse functions and find out what happens when this migration process malfunctions. This research has important implications both with regards to pathogen clearance and autoimmunity, with potential therapeutic applications.