An Immunomodulatory Role for CD4(+)CD25(+) Regulatory T Lymphocytes in Hepatitis C Virus Infection

Hepatology. 2004 Nov;40(5):1062-71. doi: 10.1002/hep.20454.

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-beta(1)) and IL-10. The inhibitory role for TGF-beta(1) was confirmed by anti-TGF-beta(1). 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies / pharmacology
  • Antibody Formation
  • Antigens, CD / metabolism
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Cell Communication
  • Epitopes
  • Hepatitis C / immunology
  • Hepatitis C / metabolism
  • Hepatitis C / pathology
  • Hepatitis C / physiopathology*
  • Hepatitis C Antigens / immunology
  • Humans
  • Immune System / physiopathology*
  • Interleukin-10 / metabolism
  • Phenotype
  • Receptors, Interleukin-2 / metabolism*
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1

Substances

  • Antibodies
  • Antigens, CD
  • Epitopes
  • Hepatitis C Antigens
  • Receptors, Interleukin-2
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Interleukin-10