Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response.
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. Subsequently, the suppressive effect of Treg on the response to HBV core antigen (HBcAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-alpha), interleukin-1-beta (IL-1beta), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-beta) 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 HBcAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-beta or exogenous IL-1beta had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-alpha partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-alpha demonstrated that TNF-alpha 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.


CONCLUSIONS
Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-alpha. Because chronic HBV patients are known to produce less TNF-alpha, these data implicate an important role for TNF-alpha in the impaired antiviral response in chronic HBV.
Stoop
Jeroen N
JN
Department of Gastroenterology and Hepatology, Erasmus MC-Rotterdam, The Netherlands.
Woltman
Andrea M
AM
Biesta
Paula J
PJ
Kusters
Johannes G
JG
Kuipers
Ernst J
EJ
Janssen
Harry L A
HL
van der Molen
Renate G
RG
D000906:Antibodies / Q000494:pharmacology; D005260:Female; D006509:Hepatitis B / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D047889:Receptors, Tumor Necrosis Factor, Type II; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013744:Tetanus Toxin / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D000906:Antibodies; D006512:Hepatitis B Core Antigens; D053583:Interleukin-1beta; D047889:Receptors, Tumor Necrosis Factor, Type II; D013744:Tetanus Toxin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10