Viral Hepatitis
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 21, 2006; 12(27): 4310-4317
Published online Jul 21, 2006. doi: 10.3748/wjg.v12.i27.4310
Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B
Yasuteru Kondo, Koju Kobayashi, Yoshiyuki Ueno, Masaaki Shiina, Hirofumi Niitsuma, Noriatsu Kanno, Tomoo Kobayashi, Tooru Shimosegawa
Yasuteru Kondo, Yoshiyuki Ueno, Hirofumi Niitsuma, Noriatsu Kanno, Tooru Shimosegawa, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
Koju Kobayashi, Tohoku University School of Health Sciences, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Masaaki Shiina, Department of Gastroenterology, Sendai Medical Center, 2-8-8 Miyagino, Miyagino-ku, Sendai 983-0045, Japan
Tomoo Kobayashi, Department of Internal Medicine, Furukawa City Hospital, Senjujimae-machi, Furukawa 919-6183, Japan
Supported by Grant from Ministry of Education, Culture, Sports, Science and Technology of Japan, No. 12877084
Correspondence to: Koju Kobayashi, Tohoku University School of Health Sciences, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. kobakoju@mail.tains.tohoku.ac.jp
Telephone: +81-22-7177929 Fax: +81-22-7177929
Received: January 13, 2006
Revised: January 28, 2006
Accepted: February 18, 2006
Published online: July 21, 2006
Abstract

AIM: To study the mechanisms of hyporesponsiveness of HBV-specific CD4+ T cells by testing TH1 and TH2 commitment and regulatory T cells.

METHODS: Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation. HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4+CD25+ cells.

RESULTS: Level of mRNAs for T-bet, IL-12R β2 and IL-4 was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4+CD25highCTLA-4+ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4+ cells and CD4+CD25+ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAg-specific TH1 antibody compared with control antibody (P < 0.01, 0.34% ± 0.12% vs 0.15% ± 0.04%). Deletion of CD4+CD25+ T cells increased the amount of HBcAg-specific TH1 antibody when compared with lymphocytes reconstituted using regulatory T cells (P < 0.01, 0.03% ± 0.02% vs 0.18% ± 0.05%).

CONCLUSION: The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.

Keywords: Hepatitis B virus; Regulatory T cells; IL-10; FOXP3; TH1