Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection

Abstract

Chronic hepatitis B virus (HBV) infection is H epatitis B virus (HBV) is a common noncyto-pathic DNA virus. Infection with HBV in adults results frequently in a self-limiting, acute hepatitis, which confers protective immunity and causes no further disease. In 10% of infected adults, HBV leads to a chronic infection. Chronic HBV infection is an important risk factor for the development of cirrhosis and hepatocellular carcinoma. Worldwide, 350 million people suffer from chronic HBV infection, and approximately 1 million people die annually from HBV-related liver disease. 1,2 T helper 1 type cytokines such as interferon ␥ (IFN-␥) and interleukin 2 are involved in cell-mediated immunity and play a crucial role in the protection against intracellular pathogens, including HBV. 3 In patients with an acute self-limiting HBV infection, a multispecific CD4 ϩ and CD8 ϩ T-cell response with a type 1 cytokine profile is important for control of the infection. 4 These multispecific T-cell responses are maintained for decades after clinical recovery. 5 In contrast, patients with a chronic HBV infection lack such a vigorous multispecific response. These patients have a weak or undetectable virus-specific T-cell response. 4 The precise mechanism responsible for this T-cell hyporesponsiveness or tolerance is still unknown. One scenario that has not been explored in relation to chronic HBV infection is the potential role of host-mediated immunosuppressive mechanisms that might be activated in the face of persistent antigenic exposure.

Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B

“…No obvious correlation was observed between ALT and HBV DNA in these patients. Earlier studies did not find a significant association between circulating CD4 ϩ CD25 ϩ Treg frequency and serum HBV DNA load in CHB patients (34,35). However, we observed that CHB patients with Ͼ10 7 copies/ml serum HBV DNA had a significant increase of circulating CD4 ϩ CD25 ϩ Treg compared with healthy controls.…”

“…This result is identical to the data from Bertoletti's group (34), but differs from the data from Janssen's group (35). A difference in methods, reagents, and samples used in the study might account for the discrepancies.…”

“…In hepatitis C virus (HCV) and HIV-infected subjects, CD4 ϩ CD25 ϩ Treg may contribute to the persistence of the infections by down-regulating HCV-or HIV-specific T cell response (29 -33). Recent data from two independent groups indicated that CD4 ϩ CD25 ϩ Treg were linked to the chronicity of the disease in patients with CHB (34,35). However, it is still controversial whether circulating CD4 ϩ CD25 ϩ Treg frequency is increased in CHB patients and whether the frequency is correlated with HBV replication due to discrepant studies.…”

“…The CD4 ϩ CD25 high subset has been counted to represent the CD4 ϩ CD25 ϩ Treg frequency in HBV and HIV-infected patients (35,43). We thus determined the frequency of CD4 ϩ CD25 ϩ Treg by measuring CD4 ϩ CD25 high subset (Fig.…”

Balance lost: T cell immunity in progressive HBV infection

“…T cells play an important role in chronic HBV infection. Indeed, several reports have reported an up-regulation of Tregs in chronic HBV infection [14][15][16][17] that were able to impair HBV-specific CD8? T cell function.…”