Dissecting the role of the ATF4 stress response in T cell-mediated inflammation

剖析 ATF4 应激反应在 T 细胞介导的炎症中的作用

基本信息

批准号：
9240576
负责人：
Binfeng Lu
金额：
$ 23.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-08 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240576
关键词：
Acute Adoptive Transfer Antigen-Presenting Cells Antioxidants Autoimmune Diseases Autoimmune Responses Automobile Driving CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Chronic Clinical Cultured Cells Data Defect Environment Equilibrium Experimental Autoimmune Encephalomyelitis Fumarates Gene Expression Profile Genes Genetic Transcription Goals ITGAX gene Immune Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Interferon Type II Interleukin-17 Knockout Mice Knowledge Mediating Methods Molecular Molecular Genetics Multiple Sclerosis Mus Myeloid Cells Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Play Production Proteins Reactive Oxygen Species Role T-Lymphocyte Testing Th1 Cells Therapeutic Transgenic Mice Wild Type Mouse activating transcription factor 4 amino acid metabolism autoreactivity bZIP Domain base biological adaptation to stress cell mediated immune response cytokine design experimental study in vivo insight knockout gene monocyte neutrophil novel therapeutic intervention public health relevance response success transcription factor

项目摘要

DESCRIPTION (provided by applicant) Reactive oxygen species (ROS) play a major role in the pathogenesis of chronic inflammatory and autoimmune diseases. It is well established that ROS modulate T cell-mediated immune responses. However, little is known about underlying molecular mechanisms of how ROS regulate T cell immune responses and how T cells adapt to high levels of ROS. Our goal is to elucidate the transcriptional network regulating T cell adaption to oxidative stress. In preliminary studies, we found ROS were elevated to much greater levels in CD4+ T cells cultured in Th1 conditions when compared to those cultured in Th0 and Th17 conditions. In further gene profiling studies, we demonstrated that ROS induced the gene expression signature of activating transcription factor-4 (ATF4) in activated Th1 cells in vitro an MOG-specific T cell in vivo. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates cellular redox state and amino acid metabolism. We demonstrated that experimental allergic encephalomyelitis (EAE) was exacerbated in ATF4 deficient mice compared with wild type (WT) mice. Consistent with clinical scores of EAE, the number of autoreactive Th1 cells was decreased whereas that of autoreactive Th17 cells was elevated in ATF4 deficient mice compared with WT mice. We further showed that in vitro ATF4 deficiency in T cells resulted in great reduction of IFN-γ production in Th1 cultures and modest reduction of IL-17 in Th17 cultures. In contrast, in vitro, ATF4 deficiency in antigen presenting cells (APC) resulted in no change in IFN-γ production in Th1 cultures but an increase in IL-17 in Th17 cultures. Based on these new findings, we hypothesize that ATF4 promotes Th1 and suppresses Th17 immune responses in pathological conditions involving the oxidative stress. To test this hypothesis, we propose the following specific aims: Specific Aim 1. Determine the T cell autonomous role of ATF4 in Th1/Th17 differentiation in vivo. Specific Aim 2. Determine the role of ATF4 within myeloid cells in T helper cell differentiation in vivo.

描述（由申请人提供）活性氧（ROS）在慢性炎症和自身免疫性疾病的发病机制中发挥着重要作用，众所周知，ROS 调节 T 细胞介导的免疫反应，但是，人们对其潜在的分子机制知之甚少。 ROS 如何调节 T 细胞免疫反应以及 T 细胞如何适应高水平的 ROS 我们的目标是阐明调节 T 细胞适应的转录网络。在初步研究中，我们发现与在 Th0 和 Th17 条件下培养的 CD4+ T 细胞相比，在 Th1 条件下培养的 ROS 水平升高得多。在进一步的基因分析研究中，我们证明 ROS 诱导基因表达。体外激活的 Th1 细胞中激活转录因子 4 (ATF4) 的特征，体内 MOG 特异性 T 细胞 ATF4 是一种碱性亮氨酸拉链 (bZip) 转录因子。我们证明，与野生型 (WT) 小鼠相比，实验性过敏性脑脊髓炎 (EAE) 加重，与 EAE 的临床评分一致，自身反应性 Th1 细胞数量减少。与 WT 小鼠相比，ATF4 缺陷小鼠的自身反应性 Th17 细胞数量升高，我们进一步表明，体外 T 细胞中 ATF4 缺陷导致 Th1 中 IFN-γ 的产生大幅减少。相反，在体外，抗原呈递细胞 (APC) 中 ATF4 缺乏导致 Th1 培养物中 IFN-γ 的产生没有变化，但 Th17 培养物中 IL-17 增加。基于这些新发现，我们认为 ATF4 在涉及氧化应激的病理条件下促进 Th1 并抑制 Th17 免疫反应。为了检验这一假设，我们提出以下具体目标：具体目标 1. 确定。 ATF4 在体内 Th1/Th17 分化中的 T 细胞自主作用具体目标 2. 确定 ATF4 在体内 T 辅助细胞分化中的作用。