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）：在转录级别，对于与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，需要细胞中的信号通路才能保持成熟的T细胞处于静止状态。如果这些途径被破坏，那么在没有抗原挑战的情况下，即使在淋巴复发宿主中，静息T细胞也会异常激活（Nat Immunol 2011）。我们的长期目标是确定积极抑制T CEL激活的这种调节基因和途径，并定义其在T细胞静止，T细胞稳态以及原发性和记忆T细胞反应中的作用。特别是在不久的将来，我们询问与T细胞静止相关的途径如何影响T细胞激活的速率和程度，从而影响响应，效应子和记忆T细胞分化的动力学和幅度。我们还将解决一个备受认识但知之甚少的过程，这是对记忆T细胞维持基础的基础：执行记忆T细胞静止是长期记忆存活的基本机制吗？这些研究将提供基本信息和新的机械见解，以指导对T细胞静止的治疗操纵与在广泛的临床环境中的激活，包括自身免疫性，传染病和疫苗发育。最近，我们将FOXP1确定为维持稳态期间天真T细胞静止的必不可少的转录调节剂。在此提案中，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强迫静止的机制。两个具体的目的是：1）确定在T CEL激活和记忆中的FOXP1调节。我们已经生成了几种FOXP1同工型特异性条件转基因小鼠以及FOXP1诱导的缺失小鼠模型。我们将利用这些新颖的增益和功能丧失的小鼠线来阐明FOXP1及其同工型在T cel活化和记忆中的作用。 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芯片测序测定法，并确定了许多新型FOXP1候选靶基因。我们将结合候选者和无偏基因组的方法，以阐明FOXP1途径如何负调节细胞生长/代谢和细胞周期进程，从而实施T细胞静止。基于我们已经建立的独特小鼠线和模型系统和FOXP1目标的独特见解，我们的研究非常重要，因为它有可能揭示几种新颖而重要的分子 FOXP1转录网络的基础机制在调节T细胞静止，激活和记忆中。