Phenotypic Changes of PD-1 and GITR in T Cells Are Associated With Hepatitis B Surface Antigen Seroclearance

Background: Regulatory T cells (Tregs) possess hepatitis B virus (HBV)-specific immunoregulatory effects in chronic HBV infection. The role of Tregs in spontaneous seroclearance of hepatitis B surface antigen (HBsAg) remains to be determined. Methods: We recruited treatment-naive chronic HBV patients achieving spontaneous HBsAg seroclearance (experimental group) and matched HBsAg-positive controls. Peripheral blood mononuclear cells were isolated using the Ficoll-Paque density gradient centrifugation method. The frequency of Tregs and inhibitory phenotypes and immunoregulatory cytokines of Tregs were detected by flow cytometry. Results: Twenty-seven patients with HBsAg seroclearance (mean age: 52.40±6.00 y, 55.6% male) and 27 matched controls were recruited. Median HBsAg and HBV DNA levels in the control group were 2.80 (1.24 to 3.43) and 3.16 (1.68 to 3.85) log IU/mL, respectively. Mean frequencies of Tregs and expressions of FoxP3 + Tregs were comparable in both groups (both P >0.05). The mean expression of programmed death 1 (PD-1) and glucocorticoid-induced TNFR family-related gene (GITR) in total CD4 + T cells were significantly downregulated in the experimental group when compared with the control group (10.62% vs. 13.85%, P =0.003; 16.20% vs. 27.02%, P =0.002, respectively). When compared with the control group, PD-1 + CD4 + Tregs expression in the experimental group was significantly downregulated (13.85% vs. 10.62%, P =0.003). A similar phenomenon was noted for GITR + CD8 + Tregs (20.16% vs. 14.08%, P =0.049). Intracellular cytokine productions showed no significant differences (all P >0.05). Conclusions: The reduced expression of PD-1 and GITR might attenuate the immunosuppressive capability of Tregs. Decreased expression on CD4 + T cells might represent an enhanced antiviral function, playing a role in initiating the “functional cure” of chronic HBV infection.