Role of hepatocytes in inducing primary CD8+ T cell activation and tolerance

众所周知，对肝脏移植物的耐受性比对其他器官移植物更容易实现，甚至跨越主要组织相容性（MHC）屏障。根据一些实验，对肝移植物的优先耐受可能是由于嵌合体的发展，嵌合体涉及在这种大小的器官中存在的非常大量的供体造血来源的乘客白细胞。然而，这样的概念并不能解释所有可用的数据，特别是那些与CD8+ T细胞，移植排斥反应的主要效应。此外，它没有考虑到肝脏具有独特的有孔内皮细胞，该内皮细胞对初始和活化的T细胞是可渗透的，也没有考虑到肝细胞本身的致耐受性。我们最近的实验表明，肝脏是CD8 T细胞的主要活化部位，正常肝脏含有大量的自身反应性CD8+ T细胞。本项目的目的是确定肝细胞对CD8+ T细胞的激活是否有助于肝移植物被接受和诱导CD8 T细胞区室耐受的惊人能力。这将表明肝脏在CD8+ T细胞的外周耐受中起着重要作用，为移植和自身免疫性疾病的治疗提供了新的治疗方法。此外，该项目还旨在在没有病毒感染的情况下产生独特的慢性肝脏炎症动物模型。在缺乏病毒携带的潜在致癌基因（如B型肝炎）的情况下，研究肝硬化和肝癌需要这样的模型。

It is well known that tolerance to liver allografts is more readily achieved than to other organ grafts, even across a major histocompatibility (MHC) barrier. According to some experiments, preferential tolerance to liver grafts may be due to development of chimerism involving the very large number of passenger leukocytes of donor hematopoietic origin present in an organ of this size. However, such a concept does not explain all the available data, particularly those relevant to CD8+ T cells, the primary effectors of graft rejection. Moreover, it does not take into account the fact that the liver possesses a unique fenestrated endothelium which is permeable to naive as well as activated T cells, nor the tolerogenic properties of hepatocytes themselves. Our recent experiments suggest that the liver is a site of primary activation for CD8 T cells and that a normal liver contains a significant number of self-reactive CD8+ T cells. The aim of this project is to determine whether activation of CD8+ T cells by hepatocytes contributes to the striking ability of liver grafts to be accepted and to induce tolerance in the CD8 T cell compartment. This would indicate that the liver plays an important role in peripheral tolerance of CD8+ T cells, providing the basis for novel therapies in transplantation and the treatment of autoimmune diseases. Moreover, this project also aims to generate a unique animal model of chronic liver inflammation in the absence of viral infection. Such a model is needed to study cirrhosis and hepatocarcinoma in the absence of potential oncogenes carried by viruses such as hepatitis B.