Project Grant R01AI186275

PD-L1 REVERSE SIGNALING IN LIVER HOMEOSTASIS AND DISEASE - 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.