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

Abstract

CD4+CD25+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self and foreign Ags, but their role in persistent viral infection has not been well-defined. In this study, we investigated whether and where CD4+CD25+ Treg contribute to the development of chronic hepatitis B (CHB). One hundred twenty-one patients were enrolled, including 16 patients with acute hepatitis B, 76 with CHB, and 29 with chronic severe hepatitis B. We demonstrated that in chronic severe hepatitis B 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. In CHB patients, circulating CD4+CD25+ Treg frequency significantly correlates with serum viral load. In acute hepatitis B patients, 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. In PBMC taken from infected patients, depletion of CD4+CD25+ Treg led to an increase of IFN-γ production by HBV-Ag-stimulated PBMC. In addition, CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV Ags, which probably reflects the generation of HBV-Ag-specific Treg in circulation and in the liver of HBV-infected patients. Together, our findings suggest that CD4+CD25+ Treg play an active role not only in modulating effectors of immune response to HBV infection, but also in influencing the disease prognosis in patients with hepatitis B.

The phenotype of hepatitis B virus–specific T cells differ in the liver and blood in chronic hepatitis B virus infection

“…[25][26][27] In contrast, we found no statistically significant increase in IL-10 ϩ CD4 ϩ T cells in the liver or blood, and the production of IL-10 was largely attributed to CD8 ϩ T cells rather than from conventional T-regulatory cells. Another possible source of IL-10 producing T cells in the liver are natural killer T (NKT) cells.…”

CD4+CD25hi regulatory T‐cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

“…However, the fact that HPV infection is necessary for the development of CIN3 and cervical carcinoma should be taken into account since various viruses have been shown to drive Treg expansion. [37][38][39][40] Indeed, we found a strong association between persistent HPV infection and increased Treg frequencies. Since most persistence patients had already a persistent infection at the time of Treg testing, it remains unclear whether the persistent HPV16 infection is responsible for the increased Treg frequency or whether increased Treg frequencies predispose to persistence.…”

“…as a percentage of CD3 1 T-cells or CD4 1 T-cells. Nevertheless, the increase of CD4 1 CD25 hi Treg frequencies among CD4 1 Tcells appears to be greater in CLL patients (10.4%) versus controls(4.5%), colon carcinoma patients (8%) versus controls (2.2%) and in hepatitis virus infected patients (6.7%) versus controls (3.6%) 5,38,43 than in the present patient group with a persistent HPV16 infection (3.8%) compared to controls (2.8%). This may be due to the fact that hepatitis virus has a more systemic effects as compared to HPV infection.…”

B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B

“…It is possible that deletion (apoptosis) and functional tolerance (exhaustion, anergy, and dysregulation of lymphokine production) of specific T cells contribute to hyporesponsiveness in hosts who are continuously exposed to high levels of viral Ags (5). In addition, CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells during chronic HBV infection have been proposed to not only modulate effectors of the immune response to HBV infection, but also to influence disease progression in patients with hepatitis B (6,7). Understanding the mechanisms underlying T cell hyporesponsiveness will have a profound influence on the establishment of an immune therapeutic regimen to break immunological tolerance and thereby terminate persistent viral infection.…”