Intrahepatic CD8+ T-Cell Failure During Chronic Hepatitis C Virus Infection *

Abstract

The precise mechanisms responsible for the failure of intrahepatic hepatitis C virus (HCV)-specific CD8 ؉ T cells to control the virus during persistent infection have not been fully defined. We therefore studied the CD8 ؉ T-cell response in 27 HLA-A2-positive patients using four previously well-defined HLA-A2-restricted HCV epitopes. The corresponding HCV sequences were determined in several patients and compared with the intrahepatic HCV-specific CD8 T here is emerging consensus that cellular immune responses play an important role in the immunopathogenesis of hepatitis C virus (HCV) infection. 1,2 Indeed, the appearance of functional HCVspecific T-cell responses is kinetically associated with control of viremia in the acute phase of infection. [3][4][5][6][7] Studies in chimpanzees revealed that virus-specific T cells accumulate in the liver and that this coincides with liver disease and viral clearance. 8,9 The central role of virusspecific CD4 ϩ and CD8 ϩ T cells in HCV clearance has further been recently demonstrated by cell depletion studies in chimpanzees. 10,11 HCV-specific T cells are also detectable in chronic hepatitis, although at a lower frequency compared with acute resolving infection. HCV-specific CD8 ϩ T-cell lines have also been generated from the human liver. [12][13][14][15] In two of these studies, cytotoxic CD8 ϩ T-cell lines could be established from approximately half of the chronically infected livers. 12,15 The long-term survival of HCV-specific CD8 ϩ T cells in the liver has also been demonstrated by major histocompatibility complex (MHC) class I tetramer analysis. While no tetramer-positive cells were found in the liver in two studies, 16,17 other studies have detected tetramer-positive CD8 ϩ T cells in livers at frequencies often exceeding 1% to 2% of intraheatic CD8 ϩ T cells, [18][19][20] indicating that these cells accumulate at the primary site of infection.The mechanisms by which HCV is able to evade the virus-specific T-cell response that is present in the infected liver are still only poorly understood. Several dif-

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…Among HCV-specific CD8 + T cells, the expression of CD27, CD45RO, and PD-1 was highly heterogeneous and did not differ between groups (data not shown). Together, these findings suggest that exhaustion of T cell functions, rather than quantitative and phenotypic differences, account for the decreased capacity of these viremics to restrict HCV replication, as previously reported (28). One characteristic of T cell exhaustion is the hierarchical loss of functions: the ability to produce IL-2 and convey cytotoxicity are lost early in the process, followed by deficient TNF-a expression, whereas IFN-g production is the function remaining intact for the longest time.…”

The phenotype of hepatitis B virus–specific T cells differ in the liver and blood in chronic hepatitis B virus infection

“…The low magnitude of HBV-specific T cells found in blood was therefore not explained by sequestration of HBV-specific T cells to the liver, which has been previously shown to be true in both HBV and HCV infections when using virus-specific tetramer ϩ T cells. 5,6,[18][19][20] It is likely that not all tetramer-positive HBV-specific T cells will produce cytokines in response to HBV peptide stimulation, as has been shown in HCV and cytomegalovirus infections. 3,19,21 Furthermore, recently published data also show that tetramer ϩ HBV-specific T cells can recover the capacity to produce IFN-␥ after inhibition of programmed death ligand-1.…”

“…5,6,[18][19][20] It is likely that not all tetramer-positive HBV-specific T cells will produce cytokines in response to HBV peptide stimulation, as has been shown in HCV and cytomegalovirus infections. 3,19,21 Furthermore, recently published data also show that tetramer ϩ HBV-specific T cells can recover the capacity to produce IFN-␥ after inhibition of programmed death ligand-1. 3 In this study we were unable to show sequestration of functional HBV-specific T cells in the liver.…”

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

“…However, the presence of tetramerϩ cells in our patients was independent of the HCV genotype, supporting the notion of cross-genotype CD8 T cell recognition. 11,15 HCV can also escape CTL recognition by mutation of target epitopes, 3,39 an early event, which remains fixed thereafter, 6,40 and determines viral persistence. 41 Moreover, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist.…”

“…The low frequency of HCV-specific CD8 T cells in the circulation of chronically infected patients [4][5][6][7][8] has been attributed to their sequestration in the liver. This is based on work on intrahepatic lymphocytes isolated from liver biopsy material and studied either after in vitro amplification [9][10][11] or directly ex vivo. [12][13][14] However, the relationship between virus-specific CTL and disease severity is controversial.…”