EGR2 in T cell tolerance

EGR2在T细胞耐受中的作用

基本信息

批准号：
8914542
负责人：
THOMAS F GAJEWSKI
金额：
$ 32.79万
依托单位：
UNIVERSITY OF CHICAGO
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：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914542
关键词：
Autoimmunity Binding Biology CCL1 gene CD28 gene CD3 Antigens CD8B1 gene Cell physiology Cell surface Cells Cellular biology ChIP-seq Data Diacylglycerol Kinase Enhancers Family Flow Cytometry Functional disorder Gene Expression Gene Expression Profiling Gene Targeting Generations Genes Goals Human Immune Immune Tolerance Immunity Immunohistochemistry In Vitro Interleukin-2 Knock-out Lipids Mediating Modeling Mutant Strains Mice Neoplasm Metastasis Pathway interactions Patients Peripheral Phosphotransferases Play Process Production Proteins Resistance Role SHPS-1 protein Semaphorins Series Surface T cell anergy T cell response T-Cell Activation T-Lymphocyte Tamoxifen Time Tumor Escape Tumor Immunity Tumor-Infiltrating Lymphocytes Up-Regulation Work anergy cancer immunotherapy chemokine class-I restricted T cell-associated molecule clinical application clinically relevant cytokine improved in vivo in vivo Model melanoma novel strategies novel therapeutics peripheral tolerance prevent programs promoter receptor research study restoration transcription factor tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): One critical mechanism of peripheral immunologic tolerance occurs through the process of T cell anergy, particularly in the tumor context. We previously have shown that upregulated expression of lipid kinases of the diacylglycerol kinase (DGK) family participate in the suppression of RasGRP-mediated Ras activation and contribute to T cell dysfunction in the anergic state. Other studies have implicated upregulation of additional negative regulatory signaling proteins, which may cooperate to maintain T cell dysfunction. Recently, through conditional knockout studies, gene expression profiling and ChIP-Seq experiments, we have identified the transcription factor EGR2 as a central regulator of expression of these negative regulatory factors in T cell anergy. Importantly, new EGR2-driven targets have emerged that are cell surface markers, which may allow flow cytometric identification of anergic cells. The major goal of this proposal is to determine the contribution o EGR2 towards peripheral tolerance to tumors. In Specific Aim 1 we will determine the effects of conditional deletion of EGR2 in peripheral T cells in vivo. Induction of T cell anergy, generation of anti-tumor immunity, and potential for evolving autoimmunity will be assessed. In Specific Aim 2, the relevance of a subset of EGR2- regulated genes in T cell biology will be investigated. We will focus on the secreted factor CCL1; the surface expression of CRTAM/LAG3/4-1BB; and the functional role of Semaphorin 7A. Whether combinations of these markers can identify anergic cells in the tumor microenvironment will be determined. In Specific Aim 3, expression of EGR2 and its targets in T cells infiltrating human melanoma will be evaluated, to move towards clinical relevance. Together, these studies will substantially broaden and deepen our understanding of EGR2 and T cell anergy in vivo, and are expected to uncover strategies that can have clinical application towards immunotherapy of cancer.

描述（由申请人提供）：通过T细胞消极的过程，尤其是在肿瘤环境中，外周免疫耐受性的一种关键机制发生在。我们先前已经表明，二酰基甘油激酶（DGK）家族的脂质激酶表达上调参与RASGRP介导的RAS激活的抑制，并在厌氧态下导致T细胞功能障碍。其他研究暗示了其他负调节信号蛋白的上调，这可能会配合以维持T细胞功能障碍。最近，通过有条件的敲除研究，基因表达分析和CHIP-seq实验，我们确定了转录因子EGR2是T细胞消音中这些负调控因子表达的中心调节剂。重要的是，已经出现了新的EGR2驱动靶标的细胞表面标记，这可能允许流式细胞仪鉴定厌氧细胞。该提案的主要目的是确定O eGR2对肿瘤外围耐受性的贡献。在特定目标1中，我们将确定EGR2在体内周围T细胞中的条件缺失的影响。将评估T细胞消极的诱导，抗肿瘤免疫力的产生以及不断发展的自身免疫性的潜力。在特定的目标2中，将研究EGR2调节基因在T细胞生物学中的相关性。我们将专注于分泌的因子CCL1； CRTAM/LAG3/4-1BB的表面表达；以及信号素7a的功能作用。这些标记物的组合是否可以鉴定在肿瘤微环境中的厌氧细胞。在特定的目标3中，将评估EGR2的表达及其在T细胞中的靶标在浸润人类黑色素瘤的T细胞中，以朝着临床相关性发展。总之，这些研究将大大扩展和加深我们对体内EGR2和T细胞消极作用的理解，并有望发现可以在癌症免疫疗法上应用临床应用的策略。