Programmed cell death protein-1

• Published in: BMC pediatrics Vol. 21; no. 1
• Main Authors: Guo, Xuangjie, Fang, Rongli, Wang, Ping, Luo, Wei, Wen, Zhe, Xu, Yiping, Zhang, Yuxia, Cai, Li, Xu, Yanhui
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 16.07.2021
• Subjects: Biliary atresia; Development and progression; Health aspects; Interferon gamma; Membrane proteins; Pediatric research; Physiological aspects; Prevention; T cells; China
• ISSN: 1471-2431; 1471-2431

Background Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-[gamma], secreted from CD4.sup.+ Th1 cells and CD8.sup.+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods Frequencies of PD-1 expressing CD4.sup.+ and CD8.sup.+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1.sup.+CD4.sup.+/CD8.sup.+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results PD-1 was significantly upregulated in CD4.sup.+ and CD8.sup.+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-[gamma] concentration in liver (PD-1.sup.+CD4.sup.+T cells in liver vs. IFN-[gamma] concentration, r = - 0.25, p = 0.05; PD-1.sup.+CD8.sup.+T cells in liver vs. IFN-[gamma] concentration, r = - 0.39, p = 0.004). Blockade of PD-1 increased IFN-[gamma] expression in CD4.sup.+ T and CD8.sup.+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 [+ or -] 3.43% vs. 21.26 [+ or -] 5.32% IFN-[gamma].sup.+ in hepatic CD4.sup.+T cells, p = 0.0003; 9.33 [+ or -] 4.03% vs. 22.55 [+ or -] 7.47% IFN-[gamma].sup.+ in hepatic CD8.sup.+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 [+ or -] 47.93 vs. 229.8 [+ or -] 45.86 [mu]mol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. Conclusions PD-1 plays a protective role in infants with BA by suppressing IFN-[gamma] production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA. Keywords: Biliary atresia, PD-1, IFN-[gamma]