Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection.
This study was performed to compare the vigor and phenotype of virus-specific CD4(+) and CD8(+) T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4(+) proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8(+) T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-gamma) staining. Furthermore, although HCV-specific cytolytic CD8(+) memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8(+) T-cell response. HCV-specific CD8(+) T cells displayed a type 1 cytokine profile characterized by production of IFN-gamma despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4(+) T cells survive and CD8(+) T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4(+) and CD8(+) T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8(+) effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus.
Chang
K M
KM
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. kmchang@mail.med.upenn.edu
Thimme
R
R
Melpolder
J J
JJ
Oldach
D
D
Pemberton
J
J
Moorhead-Loudis
J
J
McHutchison
J G
JG
Alter
H J
HJ
Chisari
F V
FV
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology
D016207:Cytokines; D010455:Peptides; D007371:Interferon-gamma