PROJECT SUMMARY The goal of this proposal is to identify the mechanism(s) by which programmed death ligand 1 (PD-L1) reverse or intracellular signaling acts as an immune regulator in the liver during both acute infection, chronic infection and chronic disease. Our studies have outlined a major role for PD-L1 reverse signaling in the control of dendritic cell (DC) migration, DC activation and in regulating T cell cytokine production. These findings are consistent with PD-L1 acting to mitigate type 1 interferon (IFN) signaling events. Using a murine model where just three amino acids in the cytoplasmic domain of PD-L1 are mutated to alanine, to limit reverse signaling, we find increased fibrosis in a murine model of Metabolic dysfunction-associated steatohepatitis (MASH) and decreased liver pathology in an acute systemic listeria infection model. Therefore, in this proposal we aim to better understand the different functions of PD-L1 reverse signaling (ie, DC migration vs activation) and how they contribute to T cell programming in listeria infection and MASH. We also aim to better understand which PD-L1 expressing cells in the liver contribute to effector T cell responses and liver fibrosis in the absence of PD-L1 reverse signaling using a murine model of MASH. Finally, we aim to address the importance of PD-L1 reverse signaling in the liver in the setting of acute versus chronic infection of LCMV. Together these Aims will define how a widely targeted immune regulatory molecule, PD-L1, functions in the liver through intracellular signaling events not previously recognized or appreciated.

PROJECT NARRATIVE In this proposal we aim to understand the impact of PD-L1 reverse signaling in the liver during acute infection and chronic disease. We will investigate consequences of PD-L1 reverse signaling to dendritic cell migration, activation and subsequent T cell priming in the setting of acute and chronic liver disease.