Adaptive Liver Tolerance via LSECs

描述 在肝脏中表达的抗原经常导致T细胞失活，导致无法消除 抗原。这被称为肝耐受，最初是在同种异体肝移植的背景下描述的， 但也是未能消除包括病毒和寄生虫在内的肝脏病原体的原因。基于 发表的工作和新的初步数据，我们提出了一个统一的模型，我们称之为适应性肝 宽容。我们的中心前提是适应性肝耐受可以解释肝脏中的免疫衰竭。 在这个模型中，肝细胞抗原直接提呈给CD8+T细胞，但通过交叉提呈 不会出现骨髓源性的APC。因此，肝细胞抗原可以与CD4+T细胞结合 仅通过MHC-II+组织细胞的交叉递呈，其中肝脏是最有力的候选者 窦状内皮细胞。然而，我们的数据显示，肝窦内皮细胞强烈上升- 调节多种免疫抑制分子。因此，十字架的有限选择- 肝细胞抗原的提呈导致CD4+T细胞耐受，从而导致CD8+T细胞耐受 精疲力竭是由于缺乏CD4+T细胞的帮助。表达的免疫抑制分子 肝窦内皮细胞对干扰素-γ有反应。因此，在这个项目中，我们将(1) 克服CD4+T细胞的失活，并测试这将逆转CD8+T细胞的预测 功能障碍；(2)直接检验干扰素-γ作用于肝窦内皮细胞的假设 细胞是免疫抑制分子表达的驱动力，也是功能性耐受的驱动力。 这些实验使用了对外源性肝细胞抗原的免疫优化模型。 通过AAV载体，因此我们还将(3)测试适应性肝耐受模型在 慢性乙肝病毒感染小鼠模型的建立。如果这一假设得到支持，那么以肝脏为目标将是合理的 肝窦内皮细胞促进自身免疫耐受，打破慢性耐受 感染。这将进一步表明，在某些情况下，抑制干扰素-γ将是有用的 增强肝脏免疫力。

Description Antigens expressed in the liver frequently lead to T cell inactivation, resulting in failure to eliminate the antigen. This is termed liver tolerance, was first described in the context of allogeneic liver transplants, but also accounts for the failure to eliminate liver pathogens including viruses and parasites. Based on published work and new Preliminary Data, we propose a unifying model which we term Adaptive Liver Tolerance. Our central Premise is that Adaptive Liver Tolerance explains immune failure in the liver. this model, hepatocellular antigens are presented directly to CD8+ T cells, but cross-presentation by bone marrow-derived APCs does not occur. Thus, hepatocellular antigens can engage CD4+ T cells only through cross-presentation by MHC-II+ tissue cells, for which the strongest candidates are liver sinusoidal endothelial cells. However, our data show that liver sinusoidal endothelial cells strongly up- regulate multiple immunosuppressive molecules. Therefore, the limited options for the cross- presentation of hepatocellular antigens leads to CD4+ T cell tolerance, and thus to CD8+ T cell exhaustion due to the lack of CD4+ T cell help. The immunosuppressive molecules that are expressed on liver sinusoidal endothelial cells are IFN-gamma responsive. Therefore, in this project we will (1) overcome the inactivation of CD4+ T cells, and test the prediction that this will reverse CD8+ T cell dysfunction; (2) directly test the hypothesis that IFN-gamma acting on the liver sinusoidal endothelial cells is the driver of the expression of immunosuppressive molecules, and of functional tolerance. These experiments use an optimized model of immunity to an extrinsic hepatocellular antigen delivered via an AAV vector, so we will also (3) test the applicability of the Adaptive Liver Tolerance model in a mouse model of chronic HBV infection. If the hypothesis is supported, it will be rational to target liver sinusoidal endothelial cells to promote tolerance in autoimmunity, and to break tolerance in chronic infection. It will further suggest that, in some circumstances, inhibition of IFN-gamma will usefully enhance immunity in the liver.