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

• 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
• 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

 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.

 说明（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起主要作用。已经确定ROS调节T细胞介导的免疫应答。然而，关于ROS如何调节T细胞免疫应答以及T细胞如何适应高水平ROS的潜在分子机制知之甚少。我们的目标是阐明调节T细胞适应的转录网络 氧化应激。在初步研究中，我们发现，与Th 0和Th 17条件下培养的CD 4 + T细胞相比，Th 1条件下培养的CD 4 + T细胞中ROS升高到更高的水平。在进一步的基因分析研究中，我们证明了ROS诱导体外活化的Th 1细胞和体内MOG特异性T细胞中转录激活因子4（ATF 4）的基因表达特征。ATF 4是一种碱性亮氨酸拉链（bZip）转录因子，调节细胞氧化还原状态和氨基酸代谢。我们证明了与野生型（WT）小鼠相比，ATF 4缺陷小鼠的实验性过敏性脑脊髓炎（EAE）加重。与EAE的临床评分一致，与WT小鼠相比，ATF 4缺陷小鼠中自身反应性Th 1细胞的数量减少，而自身反应性Th 17细胞的数量增加。我们进一步表明，体外T细胞中的ATF 4缺陷导致Th 1培养物中IFN-γ产生的大幅减少和Th 17培养物中IL-17的适度减少。相反，在体外，抗原呈递细胞（APC）中的ATF 4缺陷导致Th 1培养物中IFN-γ产生无变化，但Th 17培养物中IL-17增加。基于这些新的发现，我们假设ATF 4在涉及氧化应激的病理条件下促进Th 1和抑制Th 17免疫应答。为了验证这一假设，我们提出了以下具体目标：具体目标1。确定ATF 4在体内Th 1/Th 17分化中的T细胞自主作用。具体目标2。确定骨髓细胞内ATF 4在体内T辅助细胞分化中的作用。