Characterization Of CD4～+CD25～+ Regulatory T Cells And Their Significance In Patients With Hepatitis B

Hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus which can cause chronic hepatitis, cirrhosis and liver cancer and infects around 350 million people worldwide. 10% of adults and 90% of children become persistent HBV carriers after the infection, and one to two million people died annually as the consequence of infection with the virus, such as liver cirrhosis and hepatocellular carcinoma. As the most affected area by HBV infection, China alone has 130 million carriers of HBV and 23 million patients with chronic hepatitis B (CHB). The mechanisms responsible for the T cell tolerance in chronic HBV infection are not completely understood.It has been revealed that CD4+CD25+ regulatory T cells (Treg) play an important role in the maintenance of immunologic tolerance to both self and foreign antigens. In hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infected subjects, CD4+CD25+Treg may contribute to the persistence of the infections by down-regulating HCV or HIV-specific T cell response. Recent data indicated that CD4+CD25+ Treg were linked to the chronicity of the disease in patients with CHB. However, it is still controversial whether circulating CD4+CD25+ Treg frequency is increased in CHB patients and whether the frequency is correlated with HBV replication due to discrepant studies. More importantly, CD4+CD25+ Treg profiles in other states of HBV infection such as acute hepatitis B (AHB) and chronic severe hepatitis B (CSHB) remain unknown, and there is a paucity of data showing Treg profiles in the liver in these disease states.For comprehending the unknown above, we investigated one hundred and twenty-one HBV infected patients in this study, including 16 patients with acute hepatitis B (AHB), 76 with chronic hepatitis B (CHB), and 29 with chronic severehepatitis B (CSHB). We investigated the association between circulating CD4+CD25+Treg and different disease states for HBV-infected patients, and the correlation between circulating CD4+CD25+ Treg and serum HBV DNA load in CHB patients. We analyzed the function of circulating CD4+CD25+ Treg in AHB and CHB patients. Furthermore, we also observed the characteristics of Treg infiltrating in the liver of the CSHB, CHB patients and health controls, and the association between Treg and other immune competent cells.We demonstrated that 1) in CSHB patients, the frequencies of CD4+CD25+Treg in both PBMC and liver-infiltrating lymphocytes were significantly increased and there was a dramatic increase of FoxP3+-cell and inflammatory cell infiltration in the liver compared with healthy controls and CHB patients. 2) In CHB patients, circulating CD4+CD25+Treg frequency has a positive correlation with serum viral load. 3) In AHB patients, the circulating CD4+CD25+Treg frequency was initially low and with time, the profile reversed to exhibit an increased number of circulating Treg in the convalescent phase and restored to normal levels upon resolution. 4) CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV-Ags and anti-CD3 monoclonal antibody.Together, our findings suggest that CD4+CD25+ Treg play an active role not only in circulating but also in liver in situ modulating effectors of immune response to HBV infection. The correlation between the CD4+CD25+ Treg profile and HBV replication or liver inflammation in chronic HBV infection suggests that the level of CD4+CD25+ Treg could be a potential prognostic factor and the liver may be a critical site for the specific inhibition of immune response by these cells.