Function of stellate cells in immunity and T cell instruction

描述：肝星状细胞（HSC，或伊藤细胞）是位于肝脏的星形细胞。到目前为止，星状细胞的主要非免疫功能包括维生素A的储存、肝血流的调节和肝纤维化的产生。我们最近证明肝星状细胞是激活T淋巴细胞的强大抗原呈递细胞（APC）。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建立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。这些发现对病毒性肝炎和疟疾等严重肝脏疾病的治疗具有启示意义。此外，我们将分析星状细胞在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的代谢物维甲酸对调节性T细胞亚群的产生很重要。此外，视黄酸会促使淋巴细胞迁移到肠道。我们提供的证据表明，星状细胞以视黄酸依赖的方式促进调节性T细胞的发育。此外，我们认为肝脏中的星状细胞诱导淋巴细胞向肠道迁移。

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.