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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection
Hepatology, Volume 53, No. 5, Year 2011
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Description
An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4hiBimhi tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-γ)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant. Conclusion: CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease. © 2011 American Association for the Study of Liver Diseases.
Authors & Co-Authors
Peppa, Dimitra
United Kingdom, London
Ucl Faculty of Medical Sciences
Nebbia, Gaia
United Kingdom, London
Ucl Faculty of Medical Sciences
Kennedy, Patrick T.F.
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Geretti, Anna María
United Kingdom, London
University College London
Dusheiko, Geoffrey M.
United Kingdom, London
University College London
Maini, Mala K.
United Kingdom, London
Ucl Faculty of Medical Sciences
United Kingdom, London
University College London
Statistics
Citations: 289
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1002/hep.24249
ISSN:
15273350
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases
Maternal And Child Health
Study Design
Cohort Study
Study Approach
Quantitative