Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection.
A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8(+) T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8(+) T cells during the acute and chronic stages of infection. Although HCV-specific CD8(+) T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8(+) T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8(+) T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCV-specific CD8(+) T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.
Radziewicz
Henry
H
Emory University School of Medicine, 954 Gatewood Road, NE, Atlanta, GA 30329, USA. arash.grakoui@emory.edu
Ibegbu
Chris C
CC
Hon
Huiming
H
Osborn
Melissa K
MK
Obideen
Kamil
K
Wehbi
Mohammad
M
Freeman
Gordon J
GJ
Lennox
Jeffrey L
JL
Workowski
Kimberly A
KA
Hanson
Holly L
HL
Grakoui
Arash
A
D000328:Adult; D015703:Antigens, CD; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D053453:Caspase 9 / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D019562:Viral Load
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053453:Caspase 9