Decoding TCF1-controlled transcriptional program that promotes memory T cell fate

解码 TCF1 控制的转录程序，促进记忆 T 细胞的命运

基本信息

批准号：
8487767
负责人：
Hai-Hui Xue
金额：
$ 18.88万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-10 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487767
关键词：
Antigens Bacteria Bioinformatics CD8B1 gene Cell Maturation Cell physiology Cells ChIP-seq Clonal Expansion Complex Coupled Data Set Defect Equilibrium Family Frequencies Gene Expression Profile Gene Proteins Generations Genes Immunity Immunologic Memory Immunotherapy Infection Control Infectious Agent Knockout Mice Knowledge Lead Link Maps Mediating Memory Molecular Molecular Target Pathway interactions Phase Play Regulator Genes Role SELL gene Signal Pathway Signal Transduction Staging T cell response T cell transcription factor 1 T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Testing Transcription Factor AP-1 Transcriptional Regulation Vaccine Adjuvant Vaccines Virus base cancer cell cell mediated immune response chromatin immunoprecipitation design functional genomics gene complementation genome-wide improved interest novel novel strategies pathogen programs public health relevance self-renewal transcription factor transcriptomics

项目摘要

DESCRIPTION (provided by applicant): CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific na¿ve CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. Among effector CD8 T cells, the KLRG1+IL-7R¿- cells are considered to be terminally differentiated cytolytic effectors, and KLRG1loIL-7R¿+ cells have increased potential to give rise to long-lasting memory CD8 T cells and deemed to be memory precursors. Among memory CD8 T cells, CD62L+ central memory T cells are more efficient in homestatic self-renewal and secondary proliferation than CD62L- effector memory T cells. The T cell factor 1 (TCF1) transcription factor is known to mediate the canonical Wnt signaling and play important roles in T cell development. In recent years, studies by us and others discovered its emerging roles in regulating mature CD8 T cell responses. Specifically, activation of the Wnt signaling pathway in CD8 T cells was sufficient to expand the memory CD8 T cell pool. Furthermore, among all the transcription factors that have been studied in CD8 T cell responses to date, TCF1 deficiency most profoundly impaired central memory T cell maturation, memory T cell persistence and secondary expansion. Our preliminary studies further revealed that albeit TCF1 was significantly downregulated in KLRG1+IL-7R¿- effector T cells, substantial expression of TCF1 was retained in KLRG1loIL-7R¿+ memory precursors and CD62L+ central memory cells. In addition, loss of TCF1 greatly diminished the frequency of memory precursors at the effector phase. Based on these findings, we hypothesize that TCF1 controls unique transcriptional programs during CD8 T cell responses and retention of TCF1 and its downstream genes in CD8 effectors favors differentiation of memory precursors and formation of self-renewing central memory T cells. We propose to test this hypothesis through the following specific aims: Specific Aim 1. To elucidate the TCF1-regulated gene regulatory circuits throughout the CD8 T cell responses. Specific Aim 2. To identify TCF1 downstream genes that promote generation of memory precursors and central memory T cells. Through these proposed studies, what we will achieve is to elucidate the molecular wiring of TCF1-controlled gene regulatory program and determine its functional importance in promoting generation of robust and long- lasting memory CD8 T cells. These systematic approaches may lead to discovery of key determinants directing CD8 effectors to a memory fate. This project will have a major impact on devising strategies to utilize Wnt- derived signals or their molecular targets to improve vaccine/adjuvant design, aiming for enhanced T cell immunity against infectious agents and malignant cells.

描述（由申请人提供）：CD8 T 细胞对于控制细胞内病原体（包括病毒和细胞内细菌）的感染至关重要，CD8 T 细胞介导的几个不同阶段的免疫反应，包括抗原特异性核酸的激活。 ve CD8 T 细胞、效应 CD8 T 细胞的克隆扩增以及记忆 CD8 T 细胞的形成。在效应 CD8 T 细胞中，KLRG1+IL-7R¿ - 细胞被认为是终末分化的溶细胞效应细胞，并且 KLRG1loIL-7R¿ + 细胞产生持久记忆 CD8 T 细胞的潜力增加，被认为是记忆 CD8 T 细胞中的前体，CD62L+ 中央记忆 T 细胞比 CD62L- 效应记忆细胞在稳态自我更新和二次增殖方面更有效。 T 细胞因子 1 (TCF1) 转录因子已知可介导经典 Wnt 信号传导，并在 T 细胞发育中发挥重要作用。近年来，我们和其他人的研究发现其在调节成熟方面的新作用。具体而言，CD8 T 细胞中 Wnt 信号通路的激活足以扩大记忆 CD8 T 细胞库。此外，在迄今为止已研究的 CD8 T 细胞反应中的所有转录因子中，TCF1 缺陷最为明显。我们的初步研究进一步表明，KLRG1+IL-7R 中的 TCF1 显着下调。 -效应T细胞，KLRG1loIL-7R中保留了TCF1的大量表达+ 记忆前体细胞和 CD62L+ 中央记忆细胞此外，TCF1 的缺失大大降低了效应器阶段记忆前体细胞的频率，我们发现 TCF1 在 CD8 T 细胞反应和 TCF1 保留期间控制着独特的转录程序。 CD8 效应子中的下游基因有利于记忆前体细胞的分化和自我更新的中央记忆 T 细胞的形成。我们建议通过以下具体目标来检验这一假设：具体目标 1. 阐明整个 CD8 T 细胞反应中 TCF1 调节的基因调控回路。具体目标 2. 识别促进记忆前体细胞和中枢记忆 T 细胞生成的 TCF1 下游基因。 TCF1 控制的基因调控程序并确定其在促进强大且持久的记忆 CD8 T 细胞生成中的功能重要性。这些系统方法可能会导致发现指导 CD8 效应器记忆命运的关键决定因素。对利用 Wnt 衍生信号或其分子靶标来改进疫苗/佐剂设计的策略设计产生影响，旨在增强 T 细胞对感染因子和恶性细胞的免疫力。