An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection

Abstract

The CD4⁺CD25⁺ regulatory T lymphocytes have been implicated in suppressing T cell immune responses. Our aim was to characterize the frequency, phenotype, function, and specificity of CD4⁺CD25⁺ T cells in hepatitis C virus (HCV) infection. Peripheral CD4⁺CD25⁺ cells from recovered (n = 15), chronic infected (n = 30), and normal control (n = 15) subjects were analyzed ex vivo for quantitation, phenotype, and effect on HCV-specific interferon gamma production and proliferation. CD4⁺CD25⁺ specificity was determined by intracellular cytokine staining for interleukin 10 (IL-10). A higher proportion of CD4⁺CD25⁺ were found in chronic infection (mean, 3.02%) when compared with recovered (1.64%, P = .001) and normal controls (2.27%, P = .02). CD4⁺CD25⁺ cells display CD45RO^high, CD45RA^low, CD28^high, CD62L^high, and CD95^high phenotype. HCV-specific interferon gamma activity was enhanced in peripheral blood mononuclear cells depleted of CD4⁺CD25⁺ and suppressed in peripheral blood mononuclear cells enriched with CD4⁺CD25⁺. Depletion of CD4⁺CD25⁺ cells also enhanced HCV-specific CD4⁺ and CD8⁺ T cell proliferation. Cytokine analysis suggested CD4⁺CD25⁺ cells secrete transforming growth factor beta (TGF-β₁) and IL-10. The inhibitory role for TGF-β₁ was confirmed by anti-TGF-β₁. Transwell studies showed CD4⁺CD25⁺ mediated suppression to be dose dependent and requiring cell contact. CD4⁺CD25⁺ cells showed HCV-specificity through IL-10 production, with a frequency ranging from 1.9% to 5.3%. A positive correlation was detected between CD4⁺CD25⁺ T cell frequency and HCV RNA titer, whereas an inverse relation was found with liver inflammatory activity. In conclusion, CD4⁺CD25⁺ T lymphocytes constitute a highly differentiated population and appear to play a role in viral persistence by suppressing HCV-specific T cell responses in a cell-cell contact manner. (Hepatology 2004;40:1062-1071.)