Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C.
Chronic hepatitis C is characterized by a weak or absent hepatitis C virus (HCV)-specific CD4(+) T-cell response in terms of antigen-specific proliferation or interferon gamma (IFN-gamma) secretion. To clarify whether this is due to the absence or functional impairment of antigen-specific CD4(+) T cells we developed an assay that relies on the induced expression of the T-cell activation marker CD25 and is therefore independent from cytokine secretion or proliferation. In 10 of 20 patients with chronic hepatitis C, a significant number of antigen-specific activated CD4(+) T cells (mean 1.06%/patient; range, 0% to 5.2% of CD4(+) T cells) could be shown, whereas antigen-specific proliferation was present in only 1 of 20 patients. IFN-gamma secretion was absent in all 13 patients tested. However, significant antigen-specific interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) secretion was present in 6 of 10 and 3 of 10 patients, respectively. In 8 patients with acute hepatitis C, irrespective of disease outcome, HCV-specific CD4(+) T cells were detected in all patients and at a significantly higher frequency (mean 3.7%/patient; range, 1.16% to 7.17%) in the first weeks of disease. A chronic course of disease was associated either with a loss of both IFN-gamma secretion and proliferation, resembling an anergic state, or a loss of T-cell proliferation followed by a rapid decline in IFN-gamma-producing cells, corresponding to exhaustion of the specific immune response. In conclusion, functional changes of HCV-specific CD4(+) T cells or failure to develop a long-lasting T-helper response may contribute to chronic hepatitis C viral persistence.
Ulsenheimer
Axel
A
Institute for Immunology, University of Munich, Germany.
Gerlach
J Tilman
JT
Gruener
Norbert H
NH
Jung
Maria-Christina
MC
Schirren
Carl-Albrecht
CA
Schraut
Winfried
W
Zachoval
Reinhart
R
Pape
Gerd R
GR
Diepolder
Helmut M
HM
D000208:Acute Disease; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000821:virology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology / Q000302:isolation & purification*; D019698:Hepatitis C, Chronic / Q000175:diagnosis* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012680:Sensitivity and Specificity
D015375:Receptors, Interleukin-2