Molecular mechanisms of Th17 plasticity in MS

MS 中 Th17 可塑性的分子机制

基本信息

批准号：
8999022
负责人：
Estelle Bettelli
金额：
$ 38.22万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
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：
2013-05-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8999022
关键词：
Aryl Hydrocarbon Receptor Autoimmune Diseases Autoimmunity Automobile Driving Binding Binding Sites CD4 Positive T Lymphocytes CNS autoimmunity Cell physiology Cells Clear Cell Collaborations DNA DNase I hypersensitive sites sequencing Deoxyribonucleases Development Disease Epigenetic Process Experimental Autoimmune Encephalomyelitis Feedback Frequencies Gene Expression Regulation Generations Genetic Health Heart Human Hypersensitivity In Vitro Individual Inflammation Inflammatory Interferon Type II Interleukin-17 Link Memory Molecular Multiple Sclerosis Mus Mutation Myelin Neuraxis Pathogenicity Patients Phenotype Play Process Production Regulation Reporter Resistance Rheumatoid Arthritis Risk Role STAT4 gene Sampling Signal Transduction Site T-Lymphocyte T-Lymphocyte Subsets Techniques Technology Testing Th1 Cells Tissues Variant Work base cytokine genome-wide genome-wide analysis in vivo inhibitor/antagonist interleukin-23 mouse model multiple sclerosis patient peripheral blood promoter receptor response tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) and its mouse model (experimental autoimmune encephalomyelitis; EAE) are autoimmune diseases of the central nervous system initiated and propagated by auto-reactive CD4+ T cells. Two subsets of CD4+ T cells, Th1 and Th17 cells have been implicated in the pathogenicity of autoimmune diseases and in particular MS. However, the relative contribution of myelin specific Th1 and Th17 cells in the development of central nervous system (CNS) autoimmunity remains controversial since neither IL-17F, IL- 17A, nor IFN-γ deficient mice are fully protected from the development of CNS autoimmunity. In contrast, IL- 23p19- and IL-23 receptor (IL-23R) deficient mice are highly resistant to the development of EAE. Furthermore, in inflamed tissues of patients with autoimmune diseases, Th cells co-expressing IFN-γ and IL-17 have been identified in significant number. Their increase frequency in target tissues during autoimmunity suggests an important role of these cells in the disease process. However, the genesis, stability and function of these cells in autoimmunity remain enigmatic. We have determined that most CNS-infiltrating T cells during the course of EAE express the IL-23R irrespective of their cytokine production (IL-17 and/or IFN-γ) because they originate from Th17 cells. We further show that IL-23 plays a critical role in Th17 plasticity as it promotes the emergence of IL-17+ IFN-γ+ T cells (Th17/g) from Th17 cells. Although Th17/g cells expressed T-bet, IFN-γ production in these cells was not controlled by T-bet or other IFN-γ-promoting transcription factors. In contrast, we identified AhR as a key transcription factor driving the production of IFN-γ by Th17 cells in response to IL-23. We have also confirmed the importance of IL-23 for the generation of these cells in human CD4+ T cells. In addition, we have initiated a genome-wide analysis of DNase hypersensitivity sites in human Th1 and Th17 cells subsets using Solexa sequencing. Our results show that we can identify transcription factors binding sites and distinguish epigenetic marks in individual T cell subsets using this technique. In this proposal, we will test our overarching hypothesis that TH17/g cells are pathogenic cells in CNS-specific autoimmunity, are driven by IL-23 through an AhR-dependent mechanism and present with selective genetic alterations in MS patients. Together the completion of this study will not only delineate the function of Th17/g cells in autoimmunity but also determine the mechanisms by which these cells are generated and can be regulated in mice and humans.

描述（由适用提供）：多发性硬化症（MS）及其小鼠模型（实验性自身免疫性脑脊髓炎； EAE）是中枢神经系统的自身免疫性疾病，由自身反应性CD4+ T细胞启动并传播。在自身免疫性疾病的致病性，尤其是MS的致病性中，已隐含了两个CD4+ T细胞的子集，Th1和Th17细胞已隐含。然而，由于IL-17F，IL-17A，IL-γ缺乏小鼠均未完全保护CNS自身免疫性的发展，因此髓磷脂特异性Th1和Th17细胞在中枢神经系统（CNS）自身免疫发展中的相对贡献仍然存在争议。相反，IL-23P19和IL-23受体（IL-23R）缺乏小鼠对EAE的发展具有高度抗性。此外，自身免疫性疾病患者的发炎组织，共同表达IFN-γ和IL-17的细胞已大量鉴定。它们在自身免疫期间目标时机的频率增加表明这些细胞在疾病过程中的重要作用。但是，这些细胞在自身免疫性中的起源，稳定性和功能仍然神秘。我们已经确定，在EAE过程中，大多数CNS浸润的T细胞表达IL-23R的细胞因子产生（IL-17和/或IFN-γ），因为它们源自Th17细胞。我们进一步表明，IL-23在TH17可塑性中起关键作用，因为它促进了Th17细胞中IL-17+ IFN-γ+ T细胞（Th17/g）的出现。尽管Th17/G细胞表达了T-bet，但这些细胞中的IFN-γ产生并未由T-BET或其他IFN-γ促进转录因子控制。相比之下，我们将AHR确定为响应IL-23的TH17细胞推动IFN-γ产生的关键转录因子。我们还证实了IL-23对于在人CD4+ T细胞中产生这些细胞的重要性。此外，我们还使用Solexa测序开始了对人Th1和Th17细胞亚群中DNase超敏性位点的全基因组分析。我们的结果表明，我们可以使用此技术来识别转录因子结合位点的结合位点，并区分单个T细胞子集中的表观遗传标记。这项建议，我们将测试我们的总体假设，即Th17/G细胞是CNS特异性自身免疫性中的致病细胞，由IL-23通过AHR依赖性机制驱动，并在MS患者中具有选择性遗传改变。总之，这项研究的完成不仅会描述自身免疫性中Th17/G细胞的功能，而且还确定了这些细胞产生的机制，并且可以在小鼠和人类中调节。