The role of the intracellular complement system - the complosome - in Th1 biology

细胞内补体系统（复合体）在 Th1 生物学中的作用

• 批准号: 10008831
• 负责人: Claudia Kemper
• 金额: $ 141.43万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008831
• 关键词: Anaphylatoxins; Autoimmune Diseases; Autoimmunity; Binding; Biology; C3 gene; C3AR1 gene; C5 gene; CD4 Positive T Lymphocytes; CD46 Antigen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Lineage; Cell physiology; Cell surface; Cells; Cellular biology; Cholesterol; Chronic; Collaborations; Complement; Complement 3a; Complement 3b; Complement Activation; Computer Simulation; Contracts; Development; Disease; Economic Burden; Equilibrium; Extracellular Space; Gene Expression; Glycolysis Induction; Goals; Health; Healthcare Systems; Human; Human Activities; Hyperactive behavior; Immune; Immunosuppressive Agents; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Integrins; Interferon Type II; Interleukin-10; KLRB1 gene; Knowledge; Malignant Neoplasms; Mediating; Metabolic; Metabolism; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Oxidative Phosphorylation; Oxygen; Patients; Pharmacology; Phenotype; Physiological; Play; Production; Publishing; Recurrence; Regulation; Regulatory T-Lymphocyte; Residencies; Resolution; Rheumatoid Arthritis; Role; STAT protein; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Th1 Cells; Tissues; United States National Institutes of Health; Work; Wound Healing; adaptive immunity; autocrine; complement 3 regulator; complement C3 precursor; complement system; cytotoxic; disability; fatty acid metabolism; human disease; microorganism; new therapeutic target; novel; novel therapeutics; receptor; reduce symptoms; response; transcription factor; virtual

We aim at understanding the role of the complosome in both initiation (IFN-gamma production) and contraction (IL-10 switching) of human Th1 responses as well as CD8+ CTL biology. A. We have now shown that the complosome and autocrine CD46 engagement is also required for normal IFN-g secretion and cytotoxic activity of human CD8+ T cell responses via regulation of fatty acid metabolism. B. Regulation of C3 and C5 gene expression: The controlled regulation of C3 and/or C5 gene expression - ideally from the cell surface - would be an additional means to manipulate Th1 and CTL responses at will. In collaboration with Steve Holland (NIAID, NIH), Mariana Kaplan (NIAMS) and Niki Moutsopolous (NIDCR), we have identified the integrin LFA-1 as a master regulator of C3 gene expression in a range of immune cells. Thus, patients with deficiency in LFA-1 (LAD-1 patients) have reduced C3 expression and defective Th1 responses - which can be rescued in vitro via provision of intracellular C3a. This work also identified the gene expression induction of a virtually complete complement system as the most significant and defining feature of tissue resident vs. circulating immune cells. We are currently actively defining the role of single complosome components in immune cell tissue residency. C. Direct regulation of IL-10 production in T cells: We have demonstrated that complosome-regulated intrinsic flux of cholesterol (and subsequent cMAF transcription factor activation) in human CD4+ T cells is required for successful IL-10 induction. We further published a computational model in which the complosome-driven expression and pairing of STAT proteins tips the balance between Th1 induction and contraction in human CD4+ T cells. D. Extension of work to natural regulatory T cells. In a project driven by Ben Afzali (NIDDK), we helped identifying a subset of natural CD161-positive regulatory T cells that have wound healing capacity. We are currently assessing the role of the complosome in nTreg activity.

我们的目的是了解的作用，在启动（IFN-γ生产）和收缩（IL-10开关）的人Th 1反应，以及CD 8 + CTL生物学的补体。 A.我们现在已经表明，补体和自分泌的CD 46接合也需要正常的IFN-γ分泌和细胞毒性活性的人CD 8 + T细胞反应，通过调节脂肪酸代谢。 B。 C3和C5基因表达的调节：C3和/或C5基因表达的受控调节-理想地来自细胞表面-将是随意操纵Th 1和CTL应答的额外手段。与Steve Holland（NIAID，NIH），Mariana Kaplan（NIAMS）和Niki Moutsopolous（NIDCR）合作，我们已经确定了整合素LFA-1作为一系列免疫细胞中C3基因表达的主要调节因子。因此，LFA-1缺乏的患者（LAD-1患者）C3表达减少，Th 1应答缺陷，这可以通过提供细胞内C3 a在体外得到挽救。这项工作还确定了几乎完整的补体系统的基因表达诱导是组织驻留免疫细胞与循环免疫细胞的最重要和最明确的特征。我们目前正在积极地确定单个补体成分在免疫细胞组织驻留中的作用。 C. T细胞中IL-10产生的直接调节：我们已经证明，人CD 4 + T细胞中补体体调节的胆固醇（以及随后的cMAF转录因子激活）的内在流量是成功诱导IL-10所必需的。 我们进一步发表了一个计算模型，其中STAT蛋白的补体驱动的表达和配对提示了人CD 4 + T细胞中Th 1诱导和收缩之间的平衡。 D.将工作扩展到天然调节性T细胞。在Ben Afzali（NIDDK）推动的一个项目中，我们帮助鉴定了具有伤口愈合能力的天然CD 161阳性调节性T细胞亚群。我们目前正在评估补体在nTreg活性中的作用。