Abstract
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 TCRαβ+ DNT (αβ DNT) and TCRγδ+ DNT (γδ 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 γδ 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). αβ DNT cell frequencies were similar for all groups. In vitro, γδ DNT cells suppressed HBV core peptide-stimulated interferon-γ and tumor necrosis factor-α production in TCRαβ+CD8+ T cells, which may require cell–cell contact, and could be partially reversed by anti-NKG2A. These findings suggest that γδ DNT cells limit CD8+ T cell response to HBV, and may impede HBeAg seroconversion in CHB.
Highlights
Worldwide, more than 350 million people have chronic hepatitis B virus (HBV) infection
Univariate logistic regression showed that Hepatitis B e antigen (HBeAg) seroconversion was associated with low baseline frequencies of both cd double-negative T (DNT) cells (P = 0.04) and HBV DNA (P = 0.005)
HBeAg Seroconversion Because the HBV-specific CD8+ T-cell response mainly occurs in the liver, which is the site of HBV replication, we investigated whether the frequency of circulating cd DNT cells reflects the frequency in the intrahepatic compartment
Summary
More than 350 million people have chronic hepatitis B virus (HBV) infection. Hepatitis B e antigen (HBeAg) seroconversion, defined as the loss of serum HBeAg with development of anti-HBe, is a stage in the evolution of chronic HBV infection, which can occur either spontaneously or as a result of antiviral therapy. For HBeAg-positive patients with chronic hepatitis B (CHB), HBeAg seroconversion is one of the primary goals of antiviral treatment, as it is associated with control of viral load, cessation of liver inflammation, decreased risk for serious sequelae, and increased survival [2]. There is little information on the cellular immune mechanisms that might be responsible for these associations These mechanisms need to be identified to allow optimizing treatment strategies in individual patients and developing novel immunotherapies to increase seroconversion rates. We focused on the CD42CD82 subset of regulatory T cells, known as double-negative T (DNT) cells
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