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

Abstract

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.

Keywords: Autoimmune liver disease; CXCR6; Function; Granzyme B; Primary biliary cirrhosis; Subpopulation; Subset; TCR; Unconventional T cells; Vδ2; γδ T cells.