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

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.

Department

Biochemistry and Molecular Medicine

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