KLF10, T regulatory cells, and atherogenesis

KLF10、调节性 T 细胞和动脉粥样硬化形成

• 批准号: 8245869
• 负责人: MARK W FEINBERG
• 金额: $ 42.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245869
• 关键词: Adhesions; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Arteriosclerosis; Atherosclerosis; Autoimmune Diseases; Base Pairing; Binding; Binding Sites; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular biology; Characteristics; Chronic; Clinical; Coculture Techniques; DNA-Binding Proteins; Development; Diabetes Mellitus; Disease; Disease Progression; Dominant-Negative Mutation; Effector Cell; Erythropoiesis; Event; Family; Gelshift Analysis; Gene Chips; Gene Expression; Genes; Health; IL2RA gene; Immune; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interferons; Knockout Mice; Lesion; Maintenance; Mediating; Methods; Molecular; Morbidity - disease rate; Multiple Sclerosis; Mus; Myocardial Infarction; Pathologic; Pathway interactions; Peripheral Vascular Diseases; Phase; Phenotype; Play; Process; Proteins; RNA Interference; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Role; Screening procedure; Self Tolerance; Series; Signal Pathway; Signal Transduction; Site; Societies; Spleen; Stimulus; Stroke; Structure; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Tissue Sample; Zinc Fingers; atherogenesis; base; chromatin immunoprecipitation; cytokine; forkhead protein; in vivo; insight; interest; member; mortality; novel; novel therapeutics; overexpression; prevent; promoter; research study; response; synthetic peptide; transcription factor; vascular inflammation; yeast two hybrid system

DESCRIPTION (provided by applicant): Arteriosclerosis and its complications are the leading cause of morbidity and mortality in Western Societies. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can be viewed, in aggregate, as an inflammatory disease process. Experimental, pathologic, and clinical observations support an essential role for CD4+ T cells in atherogenesis. Recent studies have shown a critical role for CD4+CD25+ T regulatory cells for inhibiting the progression of atherosclerosis, an effect dependent in part on TGF-2 signaling. However, the mechanisms underlying the acquisition of a T regulatory cell phenotype remain poorly understood. We have identified a member of the Krupple-like family of zinc finger class of transcription factors termed KLF10 as highly expressed in T regulatory cells expressing the forkhead transcription factor Foxp3, the most specific marker for cells that possess T regulatory suppressive function. KLF10 is robustly induced in CD4+CD25- cells in response to TGF-2 treatment and decreased by pro-inflammatory stimuli in response to T cell receptor activation. Consistently, KLF10 expression is reduced in spleens of atherosclerotic-prone ApoE-deficient mice. Overexpression of KLF10 in CD4+CD25- cells potently induced the T regulatory cell functional marker Foxp3 and suppressed co- cultured CD4+CD25- effector cells. In contrast, KLF10 potently inhibits pro- inflammatory T cell signaling responses mediated by activated NFAT1 (NFATc2). These observations have led us to the central hypothesis that KLF10 serves as a critical modulator of T regulatory function and atherosclerosis. In AIM1 of this proposal we explore the mechanistic basis for KLF10's ability to induce Foxp3 gene expression. In AIM2, we examine the ability of KLF10 to inhibit T cell receptor signaling events through NFAT1. Finally, in AIM3, we assess the consequences of KLF10 deficiency on the development of atherosclerosis and on T regulatory cell function. These studies will provide important insights regarding the role of KLF10 in T regulatory cell biology. The results of these studies are of considerable scientific interest and may serve as the basis for novel therapeutic strategies to suppress T cell activation, atherosclerosis, and autoimmune diseases. PUBLIC HEALTH RELEVANCE: The accumulation in the vessel wall of specific types of immune cells termed, T lymphocytes, is a characteristic feature seen in atherosclerosis (and other chronic inflammatory diseases), an effect that may promote disease progression leading to heart attack, stroke, or peripheral vascular disease. We have identified a novel gene, termed KLF10, that is highly expressed in cells that dampen the inflammatory response, called T regulatory cells, and our studies indicate that KLF10 may act to promote T regulatory cell function. The experiments proposed in this study will examine in detail the mechanisms by which KLF10 induces the T regulatory cell suppressive phenotype and its role in experimental atherosclerosis in vivo.

描述（由申请人提供）：动脉硬化及其并发症是西方社会发病和死亡率的主要原因。动脉粥样硬化的病变代表了一系列高度特异性的细胞和分子反应，这些反应可将其视为炎症性疾病过程。实验，病理和临床观察结果支持CD4+ T细胞在动脉粥样硬化中的重要作用。最近的研究表明，CD4+ CD25+ T调节细胞在抑制动脉粥样硬化的进展方面具有关键作用，这部分取决于TGF-2信号传导。然而，收购T调节性细胞表型的基础机制仍然很少理解。我们已经确定了称为KLF10的锌指转录因子的Krupple样家族的成员，该家族在表达叉子转录因子FOXP3的T调节细胞中高度表达，这是具有T调节抑制功能的细胞最特异性标记。响应TGF-2治疗后，在CD4+CD25-细胞中强烈诱导KLF10，并因响应T细胞受体激活而降低了促炎性刺激。一致地，在动脉粥样硬化易缺陷的小鼠的脾脏中，KLF10的表达降低。 CD4+CD25-细胞中KLF10的过表达有效诱导T调节细胞功能标记FOXP3，并抑制了共培养的CD4+CD25-效应细胞。相比之下，KLF10有效抑制促炎性T细胞信号传导反应，由活化的NFAT1（NFATC2）介导。这些观察结果使我们提出了一个中心假设，即KLF10是T调节功能和动脉粥样硬化的关键调节剂。在该提案的AIM1中，我们探讨了KLF10诱导FOXP3基因表达能力的机械基础。在AIM2中，我们检查了KLF10通过NFAT1抑制T细胞受体信号传导事件的能力。最后，在AIM3中，我们评估了KLF10缺乏症对动脉粥样硬化发展和T调节细胞功能的后果。这些研究将提供有关KLF10在调节细胞生物学中的作用的重要见解。这些研究的结果具有相当大的科学兴趣，可以作为抑制T细胞激活，动脉粥样硬化和自身免疫性疾病的新型治疗策略的基础。公共卫生相关性：称为T淋巴细胞的特定类型的免疫细胞的血管壁积聚，是动脉粥样硬化（以及其他慢性炎症性疾病）中看到的一种特征，这种作用可能促进疾病的进展，导致心脏病，中风或外周血管疾病。我们已经确定了一种称为KLF10的新型基因，该基因在抑制炎症反应的细胞中高度表达，称为T调节细胞，我们的研究表明，KLF10可以起到促进T调节细胞功能的作用。本研究中提出的实验将详细研究KLF10诱导调节细胞抑制表型及其在体内实验动脉粥样硬化中的作用的机制。