In this study, by using a series of samples from HBV-infected patients and a longitudinal cohort of CHB patients with NA treatment, we showed that patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure have an upregulation of immune-suppressive features (PD-1, CTLA4, and GITR) in circulating CD4+CXCR5−FOXP3+ T cells in response to HBV antigen stimulation. Here, CTLA4 is linked to Hepatic failure.