Expansion of hepatitis C-specific CD4⁺CD25⁺ regulatory T cells after viral clearance: A mechanism to limit collateral damage?

Background: Data from rodent models suggest that a subpopulation of CD4⁺ T cells, characterized by the constitutive expression of CD25, play a key role in regulating many immune responses. Human CD4⁺CD25⁺ T cells also appear to possess a regulatory function, but their role in infections is not fully defined. Objectives: We sought to explore the possibility of a role for CD4⁺CD25⁺ T cells in controlling immunity to hepatitis C virus (HCV). We hypothesized that CD4⁺CD25⁺ T cells might account for the paucity of immune responses measurable in chronically viremic patients by suppressing the immune responses to HCV antigens. Methods: We compared the responses of PBMCs to 3 different recombinant HCV antigens before and after depletion of CD25⁺ cells in 15 chronically viremic patients, 14 nonviremic HCV antibody-positive subjects, and 14 healthy control subjects. We also tested the ability of CD4⁺CD25⁺ T cells purified from HLA-matched viremic or nonviremic blood to suppress the responses of HCV epitope-specific T-cell clones. Results: To our surprise, depletion of peripheral blood CD25⁺ cells led to a pronounced increase in proliferation of and IFN-γ production by PBMCs only in nonviremic patients. Furthermore, the CD4⁺CD25⁺ T cells purified from HLA-matched nonviremic blood (in contrast to CD4⁺CD25⁺ T cells isolated from chronically viremic blood) inhibited the responses of HCV epitope-specific T-cell clones. Conclusion: HCV-specific CD4⁺CD25⁺ regulatory T cells appear to accompany successful viral clearance.