This Project Summary/Abstract was originally submitted with R01 AI186275 and is included here unchanged to satisfy submission system requirements. 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.

This Project Narrative was originally submitted with R01 AI186275 and is included here unchanged to satisfy submission system requirements. 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.