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


  • Potential conflict of interest: J.L.H. is on the speakers' bureau of, and has received research support grants from, Bristol-Myers Squibb, Novartis, GlaxoSmithKline, and Roche. N.V.N. is an employee of Novartis.

  • This study was supported by grants from the Major Science and Technology Special Project of China (2012ZX10002-003 and 2011CB946100) and the Natural Science Foundation of China (30830091 and 81270025).

Address reprint requests to: Jinlin Hou, M.D., Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou 510515, China. E-mail:; fax: +86-20-87719653; or Yu Zhang, Ph.D., Department of Immunology, Peking University Health Science Center, No. 38 Xue Yuan Road, Beijing 100191, China. E-mail:; fax: +86-10-82801436.


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)