Negative regulatory pathways in T cell quiescence and T cell response

T 细胞静止和 T 细胞反应中的负调控途径

基本信息

批准号：
8549950
负责人：
Hui Hu
金额：
$ 24.25万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549950
关键词：
Address Affect Antigens Ascaridil Autoimmunity Biological Assay Biological Models Cell Cycle Cell Cycle Progression Cell Lineage Cell Maintenance Cell Size Cell division Cells Cellular Immunity ChIP-seq Clinical Communicable Diseases Data Development Future Gene Expression Profiling Gene Targeting Genetic Transcription Goals Growth Homeostasis Immune response Immunity Kinetics Life Maintenance Mature T-Lymphocyte Memory Metabolism Molecular Mus Pathway interactions Play Process Proliferating Protein Isoforms Proteins Receptor Signaling Regulation Regulator Genes Regulatory Pathway Research Rest Retinoblastoma Protein Role Signal Pathway Staging Supporting Cell T cell differentiation T cell response T memory cell T-Cell Activation T-Cell Development T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Therapeutic Transcriptional Regulation Transgenic Mice antigen challenge base cell growth genome-wide insight long term memory loss of function member mouse model novel public health relevance response transcription factor vaccine development

项目摘要

DESCRIPTION (provided by applicant): At the transcriptional level, little is known about the pathways that are associated with the active maintenance of T cell quiescence. We recently showed that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state; if these pathways are disrupted, resting T cells become aberrantly activated even in lympho-replete hosts in the absence of antigen challenge (Nat Immunol 2011). Our long-term goals are to identify such regulatory genes and pathways that actively restrain T cel activation, and to define their roles in T cell quiescence, T cell homeostasis, and in primary and memory T cell responses. In the immediate future, specifically, we are asking how the pathways associated with T cell quiescence impact the rate and extent of T cell activation, thereby affecting the kinetics and magnitude of the response and effector and memory T cell differentiation. We will also address a long-recognized but poorly understood process that is fundamental to the maintenance of memory T cells: is enforcing memory T cell quiescence an essential mechanism for long-term memory survival? The studies will provide fundamental information and new mechanistic insights to guide therapeutic manipulation of T cell quiescence versus activation in a broad range of clinical settings including autoimmunity, infectious diseases, and vaccine development. Recently we have identified Foxp1 as an essential transcription regulator for maintaining the quiescence of naive T cells during homeostasis. In this proposal, we will determine the role of Foxp1 proteins in the antigen-induced T cell response and elucidate the mechanisms whereby Foxp1 enforces quiescence. The two specific aims are: 1) Determine the regulation of Foxp1 on T cel activation and memory. We have generated several Foxp1 isoform-specific conditional transgenic mice as well as a Foxp1 inducible deletion mouse model. We will utilize these novel gain- and loss-of-function mouse lines to elucidate the role of Foxp1 and its isoforms in T cel activation and memory. 2) Elucidate the molecular mechanisms by which Foxp1 enforces T cell quiescence. Recently we have established a genome-wide Foxp1 ChIP-sequencing assay and identified a number of novel Foxp1-candidate target genes. We will combine both candidate and unbiased genome-wide approaches to elucidate how the Foxp1 pathway negatively regulates cell growth/metabolism and cell cycle progression, thereby enforcing T cell quiescence. Based on the unique mouse lines and model systems that we have established and the unique insights of Foxp1 targets, our study is highly significant as it has the potential to reveal several novel and important molecular mechanisms underlying the transcriptional network of Foxp1 in regulating T cell quiescence, activation and memory.

描述（由申请人提供）：在转录水平上，人们对与 T 细胞静止的主动维持相关的途径知之甚少。我们最近表明，细胞内在信号通路是维持成熟 T 细胞处于静止状态所必需的；如果这些途径被破坏，即使在没有抗原攻击的情况下，即使在淋巴细胞充足的宿主中，静息 T 细胞也会异常激活 (Nat Immunol 2011)。我们的长期目标是识别主动抑制 T 细胞激活的调节基因和通路，并确定它们在 T 细胞静止、T 细胞稳态以及初级和记忆 T 细胞反应中的作用。具体而言，在不久的将来，我们要问的是与 T 细胞静止相关的通路如何影响 T 细胞激活的速率和程度，从而影响反应以及效应和记忆 T 细胞分化的动力学和幅度。我们还将讨论一个长期被认可但知之甚少的过程，该过程对于维持记忆 T 细胞至关重要：强制记忆 T 细胞静止是长期记忆存活的重要机制吗？这些研究将提供基本信息和新的机制见解，以指导在包括自身免疫、传染病和疫苗开发在内的广泛临床环境中 T 细胞静止与激活的治疗操作。最近，我们发现 Foxp1 是一种重要的转录调节因子，可在稳态过程中维持初始 T 细胞的静止。在本提案中，我们将确定 Foxp1 蛋白在抗原诱导的 T 细胞反应中的作用，并阐明 Foxp1 强制静止的机制。两个具体目标是： 1) 确定 Foxp1 对 T 细胞激活和记忆的调节。我们已经生成了几种 Foxp1 异构体特异性条件转基因小鼠以及 Foxp1 诱导缺失小鼠模型。我们将利用这些新的功能获得和丧失的小鼠系来阐明 Foxp1 及其亚型在 T 细胞激活和记忆中的作用。 2) 阐明Foxp1强制T细胞静止的分子机制。最近，我们建立了全基因组 Foxp1 ChIP 测序分析，并鉴定了许多新的 Foxp1 候选靶基因。我们将结合候选和无偏全基因组方法来阐明 Foxp1 通路如何负向调节细胞生长/代谢和细胞周期进程，从而强制 T 细胞静止。基于我们建立的独特的小鼠品系和模型系统以及对Foxp1靶点的独特见解，我们的研究具有非常重要的意义，因为它有可能揭示一些新颖且重要的分子 Foxp1 转录网络调节 T 细胞静止、激活和记忆的机制。