Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis.

In hepatitis C virus (HCV) infection, the Th1-type immune response is involved in liver injury. A predominance of immunosuppressive regulatory T cells (Treg) is hypothesized in patients with persistently normal alanine aminotransferase (PNALT). Our aim was to clarify the role of Treg in the pathogenesis of PNALT. Fifteen chronically HCV-infected patients with PNALT, 21 with elevated ALT (CH) and 19 healthy subjects (HS) were enrolled. We determined naturally-occurring Treg (N-Treg) as CD4+CD25high+FOXP3+ T cells. The expression of FOXP3 and CTLA4 in CD4+CD25high+ cells was quantified by real-time reverse transcriptase-polymerase chain reaction. Bulk or CD25-depleted CD4+ T cells cultured with HCV-NS5 loaded dendritic cells were assayed for their proliferation and cytokine release. We examined CD127-CD25-FOXP3+ cells as distinct subsets other than CD25+ N-Treg. The frequencies of N-Treg in patients were significantly higher than those in HS. The FOXP3 and CTLA4 transcripts were higher in PNALT than those in CH. The depletion of CD25+ cells enhanced HCV-specific T cell responses, showing that co-existing CD25+ cells are suppressive. Such inhibitory capacity was more potent in PNALT. The frequency of CD4+CD127-CD25-FOXP3+ cells was higher in CH than those in PNALT. Treg are more abundant in HCV-infected patients, and their suppressor ability is more potent in patients with PNALT than in those with active hepatitis.

Impaired ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T-cell response in chronic hepatitis C virus infection.

In interferon-alpha (IFN-alpha)/ribavirin combination therapy for chronic hepatitis C (CHC), an enhanced T helper 1 (Th1) response is essential for the eradication of hepatitis C virus (HCV). We aimed to elucidate the role of IFN-alpha or IFN-alpha/ribavirin in dendritic cell (DC) ability to induce Th1 response in HCV infection. We generated monocyte-derived DC from 20 CHC patients and 15 normal subjects driven by granulocyte-macrophage colony-stimulating factor and interleukin 4 (IL-4) without IFN-alpha (GM/4-DC), with IFN-alpha (IFN-DC), with ribavirin (R-DC) or with IFN-alpha/ribavirin (IFN/R-DC) and compared their phenotypes and functions between the groups. We also compared them in 14 CHC patients between who subsequently attained sustained virological response (SVR) and who did not (non-SVR) by 24 weeks of IFN-alpha/ribavirin therapy. Compared with GM/4-DC, IFN-DC displayed higher CD86 expression, but lesser ability to secrete IL-10 and were more potent to prime CD4(+) T cells to secrete IFN-gamma and IL-2. Such differences were more significant in healthy subjects than in CHC patients. No additive effect of ribavirin was observed in DC phenotypes and functions in vitro either which was used alone or in combined with IFN-alpha. However, in the SVR patients, an ability of IFN/R-DC to prime T cells to secrete IFN-gamma and IL-2 was higher than those of IFN-DC and those of IFN/R-DC in the non-SVR group, respectively. In conclusion, DC from CHC patients are impaired in the ability to drive Th1 in response to IFN-alpha. Such DC impairment is restored in vitro by the addition of ribavirin in not all but some patients who cleared HCV by the combination therapy.