Intrahepatic Tissue-Resident CD8⁺ T-Cell Programmes Associate With Fibrosis and Local Immune Remodelling in...

Autoimmune hepatitis is an immune-mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue-resident memory T cells mediate organ-specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue-residency-associated T-cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood.

Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction-associated steatotic liver disease and 20 surgical patients providing non-inflamed adjacent non-tumorous liver tissue. Multiparameter flow cytometry assessed tissue-residency markers, T-cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters.

Autoimmune hepatitis was associated with compartment-specific remodelling of T-cell differentiation states and intrahepatic enrichment of CD8⁺ T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8⁺ T cells exhibited an interferon-γ-dominant cytokine profile, whereas CD4⁺ T cells showed broader interferon-γ-, interleukin-17A- and interleukin-4-associated responses. Despite the enrichment of tissue-residency-associated CD8⁺ T cells, cytokine-producing CD8⁺ T-cell populations with and without a tissue-resident memory phenotype contributed comparably to the hepatic T-cell compartment. Tissue-residency-associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon-γ-positive intrahepatic CD8⁺ T cells correlated inversely with fibrosis.

Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8⁺ tissue-resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.