# PD-L1 reverse signaling in liver homeostasis and disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $582,734

## Abstract

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.

## Key facts

- **NIH application ID:** 10995881
- **Project number:** 1R01AI186275-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Beth Ann Tamburini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,734
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995881

## Citation

> US National Institutes of Health, RePORTER application 10995881, PD-L1 reverse signaling in liver homeostasis and disease (1R01AI186275-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10995881. Licensed CC0.

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