Increased Circulating Follicular Regulatory T-Like Cells May Play a Critical Role in Chronic Hepatitis B Virus Infection and Disease Progression.

Follicular helper T cells (TFH) and follicular regulatory T cells (TFR), subsets of T cells, co-regulate the reactions of germinal center (GC) B cells. TFH provide help to the GC response, while the TFR suppress those processes. Nevertheless, the role of circulating TFR (cTFR) and circulating TFH (cTFH) in chronic hepatitis B virus (HBV) infection remains limited. Twenty healthy controls (HCs), 24 patients with chronic hepatitis B (CHB), 23 with HBV-related liver cirrhosis (LC), and 18 with HBV-related hepatocellular carcinoma were enrolled in our study between October 2015 and September 2016. We detected the frequencies of cTFR-like cells and cTFH-like cells, the percentage of programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), and interleukin-21 (IL-21) expressed on circulating CD4(+)CXCR5(+) T cells by flow cytometry. Compared to the HC group, the percentage of cTFR-like cells and ratio of cTFR-like/cTFH-like were significantly increased in patients with HBV infection. A raised percentage of PD-1 on circulating CD4(+)CXCR5(+) cells and decreased IL-21-producing circulating CD4(+)CXCR5(+) cells were observed in CHB and LC. The production of IL-21 by circulating CD4(+)CXCR5(+) cells was significantly higher in HBeAg negative group than the positive one. Patients with high levels of alanine aminotransferase and HBV-DNA accompanied increased CXCR5(+)PD-1(+)CD4(+) T cells. In addition, the frequency of cTFR-like cells and the ratio of cTFR-like/cTFH-like were positively correlated with FIB-4 and APRI. Increased cTFR-like cells and impairment of circulating CD4(+)CXCR5(+) T cells might participate in HBV chronic infection and HBV-related diseases.