Sha Chen1,2,3, Tingting Lv1,2,3, Guangyong Sun4,5,6, Shuxiang Li1,2,3, Weijia Duan1,2,3, Chunpan Zhang4,5,6, Hua Jin4,5,6, Dan Tian4,5,6, Mingyang Li4,5,6, Shan Shan1,2,3, Hong Ma1,2,3, Xiaojuan Ou1,2,3, Hong You1,2,3, Dong Zhang7,8,9, Jidong Jia10,11,12. 1. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, 100050, China. 2. Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing, China. 3. National Clinical Research Center for Digestive Diseases, Beijing, China. 4. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 5. Beijing Clinical Research Institute, Beijing, China. 6. Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China. 7. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. zhangd@ccmu.edu.cn. 8. Beijing Clinical Research Institute, Beijing, China. zhangd@ccmu.edu.cn. 9. Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China. zhangd@ccmu.edu.cn. 10. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, 100050, China. jia_jd@ccmu.edu.cn. 11. Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing, China. jia_jd@ccmu.edu.cn. 12. National Clinical Research Center for Digestive Diseases, Beijing, China. jia_jd@ccmu.edu.cn.
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 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 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 TCRγδlow subset may migrate to the liver via the CXCR6-CXCL16 axis and be involved in the pathogenesis of PBC by increasing GZMB production.
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 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 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 TCRγδlow subset may migrate to the liver via the CXCR6-CXCL16 axis and be involved in the pathogenesis of PBC by increasing GZMB production.