Reciprocal alterations in circulating and hepatic gamma–delta T cells in patients with primary biliary cholangitis

Background and aims Gamma–delta (γδ) T cells are involved in the development of diverse liver and autoimmune diseases, whereas the role of γδ T cells in primary biliary cholangitis (PBC) remains unclear. Methods We analyzed the number, phenotypes, and functional molecules of both circulating and hepatic γδ T cells in PBC patients and healthy controls (HCs) by flow cytometric analysis and immunohistochemistry. Results We identified two distinct functional subsets of circulating γδ T cells according to the CD3/TCRγδ complex: the TCRγδ high and TCRγδ low subsets. Approximately, three-quarters of cells in the TCRγδ high subset were Vδ1 T cells, while Vδ2 T cells were enriched in the TCRγδ low subset in HCs. The frequency and absolute number of circulating TCRγδ low cells were significantly decreased in PBC patients compared with HCs ( p < 0.001). Furthermore, the frequency of TCRγδ low cells was correlated with disease severity and ursodeoxycholic acid (UDCA) response. TCRγδ low cells exhibited a similar apoptotic and proliferative phenotype, but enhanced liver-homing chemokine receptor (CXCR6) expression in PBC patients compared with HCs. In addition, circulating TCRγδ low cells were more activated and produced higher granzyme B (GZMB) in PBC patients compared with HCs. Finally, compared with heathy liver controls, hepatic γδ T cells were increased and infiltrated in the inflamed portal tracts in PBC liver. Furthermore, the number of hepatic γδ T cells was correlated with cholestatic markers and UDCA response. Conclusion The circulating TCRγδ low subset may migrate to the liver via the CXCR6-CXCL16 axis and be involved in the pathogenesis of PBC by increasing GZMB production.