Herein, by a series of patients with chronic HBV infection in both cross-sectional treatment-naïve cohorts and longitudinal telbivudine treatment follow-up cohorts, we revealed that circulating CD4+CXCR5−FOXP3+ T cells exhibited an upregulation of immunosuppressive features (programmed death receptor-1 (PD-1), CTLA4, glucocorticoid-induced tumor necrosis factor receptor (GITR)) in patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure. Here, CTLA4 is linked to Hepatic failure.