Opposite regulation of intestinal and intrahepatic CD8 T cells controls alcohol-associated liver disease progression

Authors

• Luca Maccioni, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Yukun Guan, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Mariia Kim, Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA.
• Maria A. Parra, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
• Brandon Peiffer, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
• Yaojie Fu, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Yang Wang, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Yu-Hong Lin, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Bryan Mackowiak, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Dechun Feng, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Andrew Cameron, Surgery - Division of Transplant Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
• Zhaoli Sun, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
• George Kunos, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
• Peter Stärkel, Department of Hepato-Gastroenterology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium.
• Bin Gao, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA bgao@mail.nih.gov.

Document Type

Journal Article

Publication Date

4-8-2025

Journal

Gut

DOI

10.1136/gutjnl-2024-334412

Keywords

ALCOHOLIC LIVER DISEASE; T LYMPHOCYTES

Abstract

BACKGROUND: Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. OBJECTIVE: We examined the regulation of intestinal and intrahepatic CD8 T lymphocytes and their contribution to ALD. DESIGN: ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific Bcl2 transgenic (Cd8 ), and Cd8 mice were subjected to chronic-plus-binge ethanol feeding. RESULTS: In ALD patients, duodenal CD8 T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8 T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8 T cells expressing activation and survival genes (eg, Bcl2). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8 T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8 T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8 T cells reversed ethanol-induced loss of duodenal CD8 T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice. CONCLUSIONS: ALD is associated with loss of duodenal CD8 T cells but elevation of intrahepatic CD8 T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8 T cells may represent a novel therapeutic strategy for ALD patients.

APA Citation

Maccioni, Luca; Guan, Yukun; Kim, Mariia; Parra, Maria A.; Peiffer, Brandon; Fu, Yaojie; Wang, Yang; Lin, Yu-Hong; Mackowiak, Bryan; Feng, Dechun; Cameron, Andrew; Sun, Zhaoli; Kunos, George; Stärkel, Peter; and Gao, Bin, "Opposite regulation of intestinal and intrahepatic CD8 T cells controls alcohol-associated liver disease progression" (2025). GW Authored Works. Paper 7084.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7084

Department

Biochemistry and Molecular Medicine