Increased hepatitis C virus (HCV)‐specific CD4 + CD25 + regulatory T lymphocytes and reduced HCV‐specific CD4 + T cell response in HCV‐infected patients with normal versus abnormal alanine aminotransferase levels

Summary CD4 + CD25 + T regulatory cells may play a role in the different clinical presentations of chronic hepatitis C virus (HCV) infection by suppressing CD4 + T cell responses. Peripheral CD4 + CD25 + T cells from chronic HCV carriers with normal and abnormal alanine aminotransferase (ALT) were analysed for specificity and effect on HCV‐specific CD4 + T cell reactivity by flow cytometry for intracellular cytokine production and proliferation assay. HCV‐specific CD4 + CD25 +high T cells consistently produced transforming growth factor (TGF)‐β but only limited amounts of interleukin (IL)‐10 and no IL‐2 and interferon (IFN)‐γ. The HCV‐specific TGF‐β response by CD4 + CD25 +high T cells was significantly greater in patients with normal ALT compared to patients with elevated ALT. In addition, a significant inverse correlation was found between the HCV‐specific TGF‐β response by CD4 + CD25 +high T cells and liver inflammation. In peripheral blood mononuclear cells (PBMC), both HCV antigen‐induced IFN‐γ production and proliferation of CD4 + T cells were greater in patients with elevated ALT compared with patients with normal ALT. Depletion of CD4 + CD25 + cells from PBMC resulted in an increase of both IFN‐γ production and proliferation of HCV‐specific CD4 + T cells that was significantly greater in patients with normal ALT levels compared with patients with elevated ALT. In addition, CD4 + CD25 + T cells from patients with normal ALT levels proved to be significantly more potent to suppress CD4 + T cell reactivity with respect to those from patients with elevated ALT. In conclusion, these data support the hypothesis that CD4 + CD25 + cells may play a role in controlling chronic inflammatory response and hepatic damage in chronic HCV carriers.