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

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 ^Bcl-2), 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.

Keywords: ALCOHOLIC LIVER DISEASE; T LYMPHOCYTES.