An immunomodulatory role for CD4 +CD25 +regulatory T lymphocytes in hepatitis C virus infection (p 1062-1071)
Roniel Cabrera, Zhengkun Tu, Yiling Xu, Roberto J. Firpi, Hugo R. Rosen, Chen Liu, David R. Nelson
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- 1) and IL-10. The inhibitory role for TGF- 1was confirmed by anti-TGF- 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. (HEPATOLOGY 2004;40:1062-1071.)
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