The central research mission of the lab is to understand the distinctive features of immune responses that are generated in the liver, and reveal aspects of T cell function that are prominent in this environment. We are driven by the central idea that liver antigens can prime T cells locally, and that such priming has distinctive requirements in terms of the cell types competent to act as APC, the need for CD4+ T cell help in CD8+ T cell responses, the involvement of the innate immune system, and the long-term fate of such liver-primed T cells. This research agenda has led us to build expertise in Kupffer cell biology, and we view these cells as central in determining whether immune responses are biased towards immunity or tolerance. Multiple important pathogens target the liver, including viral hepatitis A, B, C and malaria. Therefore, we are interested in the immune responses to such pathogens, and seek to model some aspects of their immunopathology in vitro. We have developed an Adeno-Associated Virus (AAV)-based model for gene delivery to hepatocytes, and find that the CD8+ T cell response to this vector may be used to study T cell-dependent hepatitis, liver injury and fibrogenesis. Thus, we are dissecting the role of T cell- and Kupffer cell-derived cytokines in the development of liver immunopathology. Since AAV is a strong candidate vector for gene therapy, our investigations are relevant to efforts to improve this type of therapy, and in particular to negate the immune response to AAV vectors