The liver is an important site for the development of an immune response against pathogens such as Hepatitis C virus (HCV) and Hepatitis B virus (HBV), as well as the main site of alcohol metabolism. Both chronic alcohol consumption and liver infection can lead to immunosuppression;however the interaction between the two is not well defined. Studies suggest that long-term alcohol exposure affects both antigen presenting cells (APCs) and also antigen-specific T cell responses. In the liver environment, multiple populations of APCs, such as the Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells, are capable of antigen presentation to CD4+ and CD8+ T cells. The capacity of these liver APCs to activate T cells within the liver makes them essential to study when evaluating the dysregulation of T cell responses by long-term alcohol exposure. I propose to first study the effects of chronic alcohol exposure on the cell biology of the liver APC populations by using multiple methods such as microscopy, western blotting, qRT-PCR, and in vitro cell assays to study antigen presentation pathways in the presence and absence of alcohol. Specifically, I will focus on autophagy and immunoproteasome induction as these pathways may be important for antigen presentation within the liver, and there is already some evidence that they are affected by alcohol in other cell types. To complement these studies on APCs, I will next study how the antigen-specific T cell response is affected by chronic alcohol exposure by determining how alcohol-treated liver APCs affect the T cell response, and functionally characterize the resulting activated T cells. These studies will provide valuable knowledge on the capability of the immune system to prime an effective T cell response against liver pathogens in the presence of long-term alcohol exposure. Furthermore, these studies will provide new insights into the use of autophagy and the immunoproteasome for intrahepatic antigen presentation.
The incidence of HCV is high among the alcohol-abusing population in the United States. The effects of chronic alcohol exposure on antigen presentation within the liver and the subsequent development of an antigen-specific T cell response against liver infection are poorly understood. In this project I will use a mouse model to assess the effects of alcohol on the generation of an effective immune response in the liver.
|Brempelis, Katherine J; Yuen, Sebastian Y; Schwarz, Nicole et al. (2017) Central role of the TIR-domain-containing adaptor-inducing interferon-? (TRIF) adaptor protein in murine sterile liver injury. Hepatology 65:1336-1351|