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The PD-L1 intracellular TSS motif limits T cell activation thereby preventing excessive fibrotic scaring during metabolic-dysfunction associated steatohepatitis 2569

Year: 2025
Type: article
Abstract: Description Recent evidence shows the TSS motif within the cytoplasmic domain of PD-L1 is critical for intracellular signaling in cancer cells; however, the consequences of cell intrinsic PD-L1 signaling in dendritic cells (DC) or the impact on T cell activation remain unknown. Our lab designed an animal model where three intracellular amino acids were mutated (TSS-AAA) (Pdl1CyMt). We found these residues necessary for (1) DC migration and (2) regulation of interferon signaling. Due to high expression of PD-L1 in the liver, we evaluated the impact of Pdl1CyMt in a murine model of metabolic associated dysfunction steatohepatitis (MASH). Surprisingly, we found a striking increase in fibrotic scaring in Pdl1CyMt mice. To understand why Pdl1CyMt mice displayed increased fibrosis we evaluated DC and T cell localization and activation after MASH developed in WT and Pdl1CyMt mice. We found, in mice harboring the Pdl1CyMt mutation, that there were fewer migratory DCs in the liver-draining lymph nodes and elevated IFNg, IL-2 and TNFa production by activated T cells in the liver. Together with recent reports outlining the clonal expansion of T cells and contribution to disease of the same murine diet model; we propose that inappropriate activation of DCs in Pdl1CyMt drives T cell activation, residency, and increased fibrosis. These data demonstrate an important regulatory mechanism driven by the intracellular domain of PD-L1 in the liver during chronic liver disease. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
DOI: 10.1093/jimmun/vkaf283.474
Language: English
Subfield: Hepatology
Field: Medicine
Open Access status: bronze
OpenAlex ID: W4416449096
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