TY - JOUR
T1 - Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response
AU - Stoop, Jeroen N.
AU - Woltman, Andrea M.
AU - Biesta, Paula J.
AU - Kusters, Johannes G.
AU - Kuipers, Ernst J.
AU - Janssen, Harry L.A.
AU - Van Der Molen, Renate G.
PY - 2007/9
Y1 - 2007/9
N2 - Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+ regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV-specific immune response. The aim of this study was to abrogate Treg-mediated suppression of the HBV-specific immune response. Therefore, Treg and a Treg-depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequendy, the suppressive effect of Treg on the response to HBV core antigen (HBeAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-α), interleukin-1-beta (IL-1β), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-β) on Treg-mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBeAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-β or exogenous IL-1β had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-α partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-α demonstrated that TNF-α had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. Conclusion: Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-α. Because chronic HBV patients are known to produce less TNF-α, these data implicate an important role for TNF-α in the impaired antiviral response in chronic HBV.
AB - Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+ regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV-specific immune response. The aim of this study was to abrogate Treg-mediated suppression of the HBV-specific immune response. Therefore, Treg and a Treg-depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequendy, the suppressive effect of Treg on the response to HBV core antigen (HBeAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-α), interleukin-1-beta (IL-1β), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-β) on Treg-mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBeAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-β or exogenous IL-1β had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-α partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-α demonstrated that TNF-α had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. Conclusion: Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-α. Because chronic HBV patients are known to produce less TNF-α, these data implicate an important role for TNF-α in the impaired antiviral response in chronic HBV.
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U2 - 10.1002/hep.21761
DO - 10.1002/hep.21761
M3 - Article
C2 - 17654744
AN - SCOPUS:34548796457
SN - 0270-9139
VL - 46
SP - 699
EP - 705
JO - Hepatology
JF - Hepatology
IS - 3
ER -
