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: 10262679
• 负责人: Claudia Kemper
• 金额: $ 162.6万
• 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/10262679
• 关键词: Algorithms; Amino Acids; Anaphylatoxins; Autoimmune Diseases; Autoimmunity; Binding; Biology; C3 gene; C3AR1 gene; CD4 Positive T Lymphocytes; CD46 Antigen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Lineage; Cell Nucleus; Cell physiology; Cell surface; Cells; Cellular biology; Chronic; Collaborations; Complement; Complement 3b; Complement Activation; Contracts; Cytosol; Data Analyses; Development; Disease; Economic Burden; Enzymes; Event; Extracellular Space; Fatty Acids; Gene Expression; Genes; Glycolysis Induction; Goals; Health; Healthcare Systems; Human; Human Activities; Hyperactive behavior; Immune; Immunity; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Integrins; Interferon Type II; Interleukin-10; Knowledge; Laboratories; Lipids; Malignant Neoplasms; Manuscripts; Mediating; Memory; Metabolic; Metabolism; Molecular; Natural Immunity; Oxidative Phosphorylation; Oxygen; Patients; Pharmacology; Phenotype; Physiological; Play; Preparation; Probability; Production; Regulation; Resolution; Rheumatoid Arthritis; Role; Scleroderma; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Th1 Cells; Time; Tissues; Work; adaptive immunity; autocrine; comparative; complement C3 precursor; complement system; cytotoxic CD8 T cells; disability; human disease; macrophage; microorganism; new therapeutic target; novel; novel therapeutics; programs; receptor; recurrent infection; reduce symptoms; response; single-cell RNA sequencing; transcription factor

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 made major progress in understanding how C3 gene expression is regulated in T and other immune cells. We found that signals mediated by the integrin LFA-1 (engaged during diapedesis of immune cells into tissues) is a master inducer of C3. In consequence, patients with deficiency in LFA-1 cannot upregulate C3 in immune cells and, thus, lack normal Th1, CTL and IL-1b producing macrophages (Kolev and West, Immunity, 2020). B. We have now also been able to detangle the exact molecular mechanisms by which the intracellular domain of CD46 induces Th1-related genes and activities in human CD4+ T cells. This occurs via direct interaction with certain metabolic enzymes in the cytosol as well as via interaction with specific transcription factors in the nucleus (manuscripts in preparation). C. We have made equal progress in understanding how the complosome co-induces IL-10 in Th1 cells and initiates their shutdown program. These novel functions of the complosome involve the controlled expression induction of metabolic enzymes regulating lipid and amino acid usage (manuscripts in preparation). D. In an attempt to understand the signaling event underlying naive and memory CD4+ and CD8+ T cell activation in unprecedented depth, we have performed the first comparative scRNA-seq analysis of human sorted T cells over time and analyzed the data utilizing a novel algorithm integrating multiple unknown multivariate probability distributions in collaboration with the Zhang laboratory at U-Penn (manuscript in preparation).

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.我们在理解C3基因表达如何在T细胞和其他免疫细胞中调节方面取得了重大进展。我们发现由整合素LFA-1介导的信号（在免疫细胞渗出到组织中期间参与）是C3的主要诱导物。因此，LFA-1缺乏的患者不能上调免疫细胞中的C3，因此缺乏正常的Th 1、CTL和IL-1b产生巨噬细胞（Kolev和West，Immunity，2020）。 B。我们现在也已经能够理清确切的分子机制，其中CD 46的胞内结构域诱导Th 1相关的基因和活动的人CD 4 + T细胞。这是通过与细胞质中某些代谢酶的直接相互作用以及与细胞核中特定转录因子的相互作用而发生的（手稿正在编写中）。 C.我们在理解补体如何在Th 1细胞中共同诱导IL-10并启动其关闭程序方面取得了同样的进展。这些新的功能涉及控制表达诱导的代谢酶调节脂质和氨基酸的使用（手稿准备）。 D.为了以前所未有的深度了解幼稚和记忆CD 4+和CD 8 + T细胞活化的信号传导事件，我们对人类分选的T细胞进行了首次比较scRNA-seq分析，并与宾夕法尼亚大学的Zhang实验室合作，利用整合多个未知多变量概率分布的新算法分析了数据。