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

Abstract

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. We analyzed the number, phenotypes, and functional molecules of both circulating and hepatic γδT cells in PBC patients and healthy controls (HCs) by flow cytometric analysis and immunohistochemistry. We identified two distinct functional subsets of circulating γδT cells according to the CD3/TCRγδ complex: the TCRγδhigh and TCRγδlow subsets. Approximately, three-quarters of cells in the TCRγδhigh subset were Vδ1 T cells, while Vδ2 T cells were enriched in the TCRγδlow subset in HCs. The frequency and absolute number of circulating TCRγδlow cells were significantly decreased in PBC patients compared with HCs (p < 0.001). Furthermore, the frequency of TCRγδlow cells was correlated with disease severity and ursodeoxycholic acid (UDCA) response. TCRγδlow 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 TCRγδlow cells were more activated and produced higher granzyme B (GZMB) in PBC patients compared with HCs. Finally, compared with heathy liver controls, hepatic γδT 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. The circulating TCRγδlow subset may migrate to the liver via the CXCR6-CXCL16 axis and be involved in the pathogenesis of PBC by increasing GZMB production.