Deciphering the cellular mechanisms promoting CD4+ T cell-dependent intrahepatic CD8+ T cell immunity

Abstract

The liver is the body’s largest internal organ and assumes many important physiological and metabolic functions. It is also well-established that the liver possesses unique immunological properties and a delicate balance between tolerance and immunity exists within this large organ. CD4 T cell help to CD8 T cells has emerged as a critical factor involved in promoting robust CD8 T cell responses against viral and tumour antigens. Studies in humans and chimpanzees indicate that CD4 T cells are critical for strong intrahepatic CD8 T cell responses and the spontaneous control of hepatitis C virus and hepatitis B virus infections. However, due to limitations of current small animal models, the precise role of CD4 help in orchestrating intrahepatic CD8 T cell responses, and the mechanisms by which CD4 help is transferred to intrahepatic CD8 T cells remains poorly understood. Using an rAAV based approach to express model antigens containing both CD4 and CD8 T cell epitopes specifically in hepatocytes, we first demonstrate that CD4 help enhances the primary expansion of CD8 T cells responding to hepatocyte expressed antigens, which is critical for the generation of a large pool of memory CD8 T cells in the liver, blood and lymphoid tissues. Importantly, we decipher a novel mechanism facilitating the transfer of CD4 help to intrahepatic CD8 T cells: cognate CD40-CD40L licensing of hepatic XCR1 cDC1s in situ within portal tracts and central veins. In deciphering this mechanism, we also uncovered a previously unrecognised interconnected myeloid cell network contained within portal tracts in the steady state and following antigen expression in the liver. Together, these discoveries yield important insights into the mechanisms governing the outcome of intrahepatic immune responses, and suggest avenues for future work, with the possibility of translational research to explore novel therapies to manipulate intrahepatic immunity and hence beneficially alter outcomes in human liver diseases.