Accumulation of dysfunctional effector CD8+ T cells in the liver of patients with chronic HCV infection.
ABSTRACT Hepatitis C virus (HCV) causes a chronic infection that can lead to fibrosis and carcinoma. Immune responses mediated by cytotoxic T lymphocytes (CTLs) could be involved in viral clearance or persistence, and therefore in determining the course of the disease.
Intrahepatic and peripheral blood CD8+T cells were obtained from 32 HCV-chronically infected patients and analysed by flow-cytometry for surface markers of differentiation, IFNgamma and TNFalpha production, degranulation capacity and perforin content, after CD3 triggering. Results were compared with those obtained from 13 patients with a non-viral liver disease.
Intrahepatic CD8+T cells of HCV-infected patients, despite their phenotype of pre-terminally and terminally differentiated effectors (CCR7-CD45RA-/+), are poorly responsive to T cell receptor (TCR)-mediated stimulation compared with those obtained from uninfected subjects. This defect correlates with the severity of fibrosis, is more pronounced in patients with ALT<1.5xN than with ALT>1.5xNU/ml, and is not evident after mitogen stimulation.
The present study describes the accumulation of hypo-responsive CD8+T cells in the liver of patients with chronic HCV infection. Understanding the mechanisms underlying this impairment may be helpful in the design of innovative strategies for HCV treatment.
- SourceAvailable from: Donald D. Anthony
[Show abstract] [Hide abstract]
- "Dolganiuc et al found that mDC induced more Tregs in HCV infected individuals, which could hamper T helper responses . Nisii et al found an accumulation of dysfunctional CD8+ T cells in livers of subjects with chronic HCV suggesting global T cell defects may be present . Defects in CD4+ helper T cells have not been reported. "
ABSTRACT: Individuals with chronic HCV infection have impaired response to vaccine, though the etiology remains to be elucidated. Dendritic cells (DC) and monocytes (MN) provide antigen uptake, processing, presentation, and costimulatory functions necessary to achieve optimal immune responses. The integrity of antigen processing and presentation function within these antigen presenting cells (APC) in the setting of HCV infection has been unclear. We used a novel T cell hybridoma system that specifically measures MHC-II antigen processing and presentation function of human APC. Results demonstrate MHC-II antigen processing and presentation function is preserved in both myeloid DC (mDC) and MN in the peripheral blood of chronically HCV-infected individuals, and indicates that an alteration in this function does not likely underlie the defective HCV-infected host response to vaccination.Cellular Immunology 10/2010; 266(2):187-91. DOI:10.1016/j.cellimm.2010.10.003 · 1.87 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.The Journal of Infectious Diseases 11/2006; 194(8):1068-77. DOI:10.1086/507681 · 5.78 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Worldwide more than 170 million people are chronically infected with the hepatitis C virus (HCV), which is a frequent cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Unlike infection with other hepatotropic viruses, only a small percentage of acute HCV infections are cleared, and most infected individuals develop lifelong HCV infection in the absence of efficient treatment. It is believed that both viral and host factors contribute to the inability of the host immune system to clear the initial infection and lead to the high propensity of chronic HCV infection.Clinics in Liver Disease 12/2006; 10(4):753-71. DOI:10.1016/j.cld.2006.08.028 · 2.70 Impact Factor