Function of stellate cells in immunity and T cell instruction

星状细胞在免疫和T细胞指令中的功能

• 批准号: 8580491
• 负责人: Florian Winau
• 金额: $ 28.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580491
• 关键词: Adoptive Transfer; All-Trans-Retinol; Animals; Antigen-Presenting Cells; Antigens; Apoptosis; Bacteria; Bacterial Infections; Biological Process; Blood flow; CCR9 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Shape; Cell physiology; Cells; Coculture Techniques; Data; Development; Diphtheria Toxin; Event; Exhibits; Food; Frequencies; Ganciclovir; Generations; Glial Fibrillary Acidic Protein; Goals; Hepatic; Hepatic Stellate Cell; Home environment; Homing; Immune response; Immunity; Immunology; In Vitro; Infection; Instruction; Integrins; Intestines; Knock-in Mouse; Listeria monocytogenes; Liver; Liver Fibrosis; Liver diseases; Location; Lymphocyte; Malaria; Measures; Mediating; Modeling; Mus; Oral; Peripheral; Physiological; Play; Prodrugs; Property; Regulation; Regulatory T-Lymphocyte; Research; Research Proposals; Role; Signaling Molecule; Site; System; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymidine Kinase; Tissues; Transgenic Mice; Tretinoin; Ursidae Family; Viral hepatitis; Vitamin A; diphtheria toxin receptor; in vivo; in vivo Model; migration; mouse model; oral tolerance; promoter; public health relevance; receptor; response; stellate cell; trafficking

Description: Hepatic stellate cells (HSC, or Ito cells) are star-shaped cells located in the liver. So far, primarily nonimmunological functions of stellate cells have been described including storage of vitamin A, regulation of hepatic blood flow and generation of liver fibrosis. We recently demonstrated that hepatic stellate cells are powerful antigen-presenting cells (APC) to activate T lymphocytes. However, the precise physiological role of stellate cells in liver immunology remains unclear due to the lack of convincing in vivo models. Therefore, the goal of this research proposal is to develop mouse models of stellate cell depletion. We will use these systems to study the impact of hepatic stellate cells on immunity and infection in vivo. Our preliminary data indicate that stellate cells mediate protection against bacterial infection of the liver. These findings bear implications for the treatment of severe liver diseases such as viral hepatitis and malaria. Moreover, we will analyze the function of stellate cells in T cell differentiation and instruction. The majority of the body's vitamin A is stored in hepatic stellate cells. A metabolite of vitamin A called retinoic acid is important for the generation of regulatory T cell subsets. Additionally, retinoic acid triggers lymphocytes to migrate to the gut. We provide evidence that stellate cells promote development of regulatory T cells in a retinoic aciddependent fashion. Moreover, we suggest that stellate cells in the liver induce migration of lymphocytes to the gut. Taken together, the APC function of hepatic stellate cells is the key to antigen-dependent T cell instruction. These instruction events determine the quality and location of immune responses. This concept describes the liver as a central check point in regulation of lymphocyte migration and response. Public Health Relevance: Hepatic stellate cells are important to trigger immune responses in the liver. Moreover, they regulate the lymphocyte traffic in the body. Thus, understanding the immunology of stellate cells will help to treat liver diseases.

描述：肝星状细胞（HSC或Ito细胞）是位于肝脏的星形细胞。迄今为止，已经描述了星状细胞的主要非免疫功能，包括储存维生素A、调节肝血流和产生肝纤维化。我们最近发现，肝星状细胞是强大的抗原提呈细胞（APC）激活T淋巴细胞。然而，由于缺乏令人信服的体内模型，星状细胞在肝脏免疫学中的确切生理作用仍不清楚。因此，本研究计划的目标是开发星状细胞耗竭的小鼠模型。我们将使用这些系统来研究肝星状细胞对体内免疫和感染的影响。我们的初步数据表明，星状细胞介导对肝脏细菌感染的保护作用。这些发现对治疗病毒性肝炎和疟疾等严重肝脏疾病具有重要意义。此外，我们还将分析星状细胞在T细胞分化和指导中的功能。人体的大部分维生素A储存在肝星状细胞中。维生素A的代谢产物视黄酸对调节性T细胞亚群的产生很重要。此外，视黄酸会触发淋巴细胞迁移到肠道。我们提供的证据表明，星状细胞促进发展的调节性T细胞在视黄酸依赖的方式。此外，我们认为，肝星状细胞诱导淋巴细胞迁移到肠道。 总之，肝星状细胞的APC功能是抗原依赖性T细胞指令的关键。这些指令事件决定免疫应答的质量和位置。这个概念描述了肝脏作为调节淋巴细胞迁移和反应的中心检查点。 公共卫生相关性：肝星状细胞对触发肝脏免疫反应很重要。此外，它们调节体内淋巴细胞的运输。因此，了解星状细胞的免疫学将有助于治疗肝脏疾病。