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

Abstract

Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. We examined the regulation of intestinal and intrahepatic CD8⁺ T lymphocytes and their contribution to ALD. 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 <i>Bcl2</i> transgenic (<i>Cd8</i> ^Bcl-2), and <i>Cd8</i> ^-/- mice were subjected to chronic-plus-binge ethanol feeding. 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, <i>Bcl2</i>). 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. 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.