An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection.
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.
Section of Hepatobiliary Diseases, Department of Medicine, University of Florida, Gainesville, FL 32610-0214, USA.
Roniel
R
Cabrera
Zhengkun
Z
Tu
Yiling
Y
Xu
Roberto J
RJ
Firpi
Hugo R
HR
Rosen
Chen
C
Liu
David R
DR
Nelson
D000906:Antibodies / Q000494:pharmacology; D000917:Antibody Formation; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002450:Cell Communication; D000939:Epitopes; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018936:Hepatitis C Antigens / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D016753:Interleukin-10 / Q000378:metabolism; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000906:Antibodies; D015703:Antigens, CD; D000939:Epitopes; D018936:Hepatitis C Antigens; D015375:Receptors, Interleukin-2; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10