TCRγδ+CD4-CD8- T Cells Suppress the CD8+ T-Cell Response to Hepatitis B Virus Peptides, and Are Associated with Viral Control in Chronic Hepatitis B

The immune mechanisms underlying failure to achieve hepatitis B e antigen (HBeAg) seroconversion associated with viral control in chronic hepatitis B (CHB) remain unclear. Here we investigated the role of CD4(-) CD8(-) T (double-negative T; DNT) cells including TCR alpha beta(+) DNT (alpha beta DNT) and TCR gamma delta(+) DNT (gamma delta DNT) cells. Frequencies of circulating DNT cell subsets were measured by flow cytometry in a retrospective cohort of 51 telbivudine-treated HBeAg-positive CHB patients, 25 immune tolerant carriers (IT), 33 inactive carriers (IC), and 37 healthy controls (HC). We found that gamma delta DNT cell frequencies did not significantly change during treatment, being lower at baseline (P = 0.019) in patients with HBeAg seroconversion after 52 weeks of antiviral therapy (n = 20) than in those without (n = 31), and higher in the total CHB and IT than IC and HC groups (P<0.001). alpha beta DNT cell frequencies were similar for all groups. In vitro, gamma delta DNT cells suppressed HBV core peptide-stimulated interferon-gamma and tumor necrosis factor-a production in TCR alpha beta(+) CD8(+) T cells, which may require cell-cell contact, and could be partially reversed by anti-NKG2A. These findings suggest that gamma delta DNT cells limit CD8(+) T cell response to HBV, and may impede HBeAg seroconversion in CHB.