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Background  T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of CD4 + CXCR5 +  TFH cells could be associated with active immunity in chronic hepatitis B (CHB) patients.    Methodology and Findings  The frequencies of peripheral blood CD4 + CXCR5 +  TFH cells, inducible T cell costimulator (ICOS), and/or programmed death 1 (PD-1) positive CD4 + CXCR5 +  TFH cells in immune-active (IA), immune-tolerant (IT) CHB, and healthy controls (HC) were characterized by flow cytometry analysis. The effect of adevofir dipivoxil treatment on the frequency of CD4 + CXCR5 +  TFH cells, the concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-21, ALT, AST, HBsAg, HBsAb, HBeAg, HBeAb and HBV loads in IA patients were determined. The potential association of the frequency of CD4 + CXCR5 +  TFH cells with clinical measures was analyzed. In addition, the frequency of splenic and liver CD4 + CXCR5 +  TFH cells in HBV-transgenic mice was examined. We found that the frequency of CD4 + CXCR5 +  TFH cells in IA patients was significantly higher than that of IT patients and HC, and the percentages of CD4 + CXCR5 +  TFH in IA patients were positively correlated with AST. Furthermore, the percentages of ICOS + , PD-1 + , and ICOS + PD-1 +  in CD4 + CXCR5 +  TFH cells in CHB patients were significantly higher than that of HC. Treatment with adefovir dipivoxil reduced the frequency of CD4 + CXCR5 +  TFH, PD-1 + CD4 + CXCR5 +  TFH cells and the concentrations of HBsAg and HBeAg, but increased the concentrations of HBsAb, HBeAb, IL-2 and IFN-γ in IA patients. Moreover, the frequency of splenic and liver CD4 + CXCR5 +  TFH cells in HBV-transgenic mice was higher than that of wild-type controls.    Conclusions  These data indicate that CD4 + CXCR5 +  TFH cells may participate in the HBV-related immune responses and that high frequency of CD4 + CXCR5 +  TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients.

High Frequency of CD4+CXCR5+ TFH Cells in Patients with Immune-Active Chronic Hepatitis B