Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection.
Generalized CD8+ T-cell impairment in chronic hepatitis C virus (HCV) infection and the contribution of liver-infiltrating CD8+ T-cells to the immunopathogenesis of this infection remain poorly understood. It is hypothesized that this impairment is partially due to reduced CD8+ T-cell activity in response to cytokines such as IL-7, particularly within the liver. To investigate this, the phenotype and cytokine responsiveness of blood- and liver-derived CD8+ T-cells from healthy controls and individuals with HCV infection were compared. In blood, IL-7 receptor α (CD127) expression on bulk CD8+ T-cells in HCV infection was no different than controls yet was lower on central memory T-cells, and there were fewer naïve cells. IL-7-induced signalling through phosphorylated STAT5 was lower in HCV infection than in controls, and differed between CD8+ T-cell subsets. Production of Bcl-2 following IL-7 stimulation was also lower in HCV infection and inversely related to the degree of liver fibrosis. In liver-derived CD8+ T-cells, STAT5 activation could not be increased with cytokine stimulation and basal Bcl-2 levels of liver-derived CD8+ T-cells were lower than blood-derived counterparts in HCV infection. Therefore, generalized CD8+ T-cell impairment in HCV infection is characterized, in part, by impaired IL-7-mediated signalling and survival, independent of CD127 expression. This impairment is more pronounced in the liver and may be associated with an increased potential for apoptosis. This generalized CD8+ T-cell impairment represents an important immune dysfunction in chronic HCV infection that may alter patient health.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.|Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Stephanie C
SC
Burke Schinkel
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Lorna
L
Carrasco-Medina
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada.|Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa, Ontario, Canada.
Curtis L
CL
Cooper
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.|Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biology, Carleton University, Ottawa, Ontario, Canada.
Angela M
AM
Crawley
D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D015851:Interleukin-7 / Q000008:administration & dosage / Q000378:metabolism*; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis* / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D050799:STAT5 Transcription Factor
C508605:IL7 protein, human; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor