Cirrhosis-associated immune dysfunction reflects impaired intestinal CD8ab⁺ intraepithelial lymphocyte compartmentalization

Abstract

Bacterial infections drive decompensation and mortality in cirrhosis, yet the mechanisms underlying cirrhosis-associated immune dysfunction remain unclear. Current models invoke adaptive immune exhaustion, whereas intestinal intraepithelial lymphocytes (IELs), which mediate epithelial surveillance and microbial containment, remain unexplored. We combined spectral flow cytometry of paired duodenal biopsies and blood, plasma proteomics, immunofluorescence and single-cell RNA sequencing in healthy volunteers and patients with compensated or decompensated cirrhosis. The healthy duodenal epithelium was dominated by CD8 alpha beta IELs, which were depleted in cirrhosis, whereas innate cytotoxic populations expanded. CD8 alpha beta IEL loss correlated with plasma markers of bacterial translocation. Residual IELs showed attenuated antimicrobial programs, confirmed by reduced granulysin protein, and enriched cytotoxic pathways. IEL depletion was accompanied by reduced CCR9 on circulating and mucosal CD8 T cells and elevated plasma CCL25. Exposing blood mononuclear cells to patient-level CCL25 concentrations reduced surface CCR9, indicating ligand-driven desensitization. In contrast, circulating lymphocytes retained functional competence and lacked exhaustion markers. Cirrhosis-associated immune dysfunction thus reflects failed intestinal compartmentalization of CD8 alpha beta T cells, linked to disruption of the CCL25-CCR9 axis, rather than systemic exhaustion.