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

• Published in: Hepatology (Baltimore, Md.) Vol. 40; no. 5; pp. 1062 - 1071
• Main Authors: Cabrera, Roniel, Tu, Zhengkun, Xu, Yiling, Firpi, Roberto J., Rosen, Hugo R., Liu, Chen, Nelson, David R.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2004; Wiley
• Subjects: Antibodies - pharmacology; Antibody Formation; Antigens, CD - metabolism; Biological and medical sciences; Case-Control Studies; 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; Cell Communication; Epitopes; Fundamental and applied biological sciences. Psychology; Hepatitis C - immunology; Hepatitis C - metabolism; Hepatitis C - pathology; Hepatitis C - physiopathology; Hepatitis C Antigens - immunology; Human viral diseases; Humans; Immune System - physiopathology; Infectious diseases; Interleukin-10 - metabolism; Liver. Bile. Biliary tracts; Medical sciences; Phenotype; Receptors, Interleukin-2 - metabolism; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1; Vertebrates: digestive system; Viral diseases; Viral diseases of the digestive system; Viral hepatitis; Check; Hepatic disease; Cellular immunity; Beta; Prevention; Specificity; Ex vivo; Immunological investigation; Dicotyledones; Angiospermae; T-Lymphocyte; Production; Viral hepatitis C; Human; Cytokine; Proliferation; Chenopodiaceae; Virus; Infection; Chronic; Phenotype; Viral disease; Digestive diseases; Frequency; Spermatophyta; Intracellular; Flaviviridae; Hepatitis C virus; Hepacivirus; Gamma interferon
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.20454

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 CD45ROhigh, CD45RAlow, CD28high, CD62Lhigh, and CD95high 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.)