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.
Project 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. 1
|Beyaz, Semir; Kim, Ji Hyung; Pinello, Luca et al. (2017) The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat Immunol 18:184-195|
|Hu, Yu; Kim, Ji Hyung; He, Kangmin et al. (2016) Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. J Exp Med 213:2759-2772|
|Kim, Ji Hyung; Hu, Yu; Yongqing, Tang et al. (2016) CD1a on Langerhans cells controls inflammatory skin disease. Nat Immunol 17:1159-66|
|Maschmeyer, Patrick; Flach, Melanie; Winau, Florian (2011) Seven steps to stellate cells. J Vis Exp :|
|Darmoise, Alexandre; Teneberg, Susann; Bouzonville, Lauriane et al. (2010) Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells. Immunity 33:216-28|
|Darmoise, Alexandre; Maschmeyer, Patrick; Winau, Florian (2010) The immunological functions of saposins. Adv Immunol 105:25-62|