Circulating Chemokine (C-X-C Motif) Receptor 5+CD4+ T Cells Benefit Hepatitis B e Antigen Seroconversion Through IL-21 in Patients With Chronic Hepatitis B Virus Infection

Given the clinical significance of hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus (HBV) infection, it is critical to elucidate the mechanisms regulating this process. In the present study, we found that the frequency of circulating chemokine (C-X-C motif) receptor 5 (CXCR5)(+)CD4(+) T cells was higher in patients who had achieved HBeAg seroconversion in both cross-sectional (P<0.001) and longitudinal (P = 0.009) studies. These cells were able to produce a significantly higher level of intracellular interleukin 21 (IL-21) after stimulation with HBV peptides in patients with telbivudine-induced HBeAg seroconversion (P=0.007). Furthermore, sorted CXCR5(+)CD4(+) T cells from HBeAg seroconverters boosted a higher frequency of antibody against hepatitis B e antigen (anti-HBe)-secreting B cells in coculture assay (P=0.011). Of note, the increase in frequency of anti-HBe-secreting B cells was abrogated by soluble recombinant IL-21 receptor-Fc chimera (P=0.027), whereas exogenous recombinant IL-21 enhanced this effect (P=0.043). Additionally, circulating CXCR5(+)CD4(+) T cells shared similar phenotypic markers, and were positively correlated in frequency with, splenic follicular T helper cells. Conclusion: Circulating CXCR5(+)CD4(+) T cells, by producing IL-21, may have a significant role in facilitating HBeAg seroconversion in patients with chronic HBV infection. (Hepatology 2013;58:1277-1286)