Phenotypic and Functional Characterization of Intrahepatic T Lymphocytes During Chronic Hepatitis C

Abstract

The pathogenesis of liver cell injury during chronic hepatitis C (CHC) is poorly understood. The cellular immune response is thought to play a key role in both inhibition of viral replication and liver pathology. However, little is currently known about which lymphocyte populations and which immune effectors contribute to or control liver damage. We investigated a panel of 15 phenotypic and functional markers of intrahepatic T-lymphocyte subsets irrespective of their antigen specificity in 48 hepatitis C virus (HCV)-infected patients and 8 healthy control subjects. Lymphocyte characteristics were evaluated from liver biopsy specimens both at gene expression level by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and by immunochemistry, in relation with the degree of liver injury and with intrahepatic HCV-RNA levels. As compared with controls, we found major changes in T-lymphocyte subsets in HCV-infected patients, with a significant decrease of T-cell antigen receptor (TCR) delta and CD56 gene expression, associated with a concomitant increase of TCRalpha and CD8beta that were correlated with cytotoxic factors, proinflammatory chemokines, and chemokine receptors including peforin, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, and CXCR3. The gene expression of CD8beta, a specific marker for conventional TCRalpha+CD8+ lymphocytes, was correlated by multivariate analysis with both alanine aminotransferase (ALT) serum levels and histologic activity index. Furthermore, CD8 staining was observed by immunochemistry in the areas of lobular and piecemeal necrosis. In contrast, no lymphocyte marker was correlated with viral load, measured both in serum and in liver. In conclusion, these results strongly suggest key roles for CD8+ T cells as effectors of liver damage during chronic HCV infection and for their inability to control viral replication.

Liver Restores Immune Homeostasis after Local Inflammation despite the Presence of Autoreactive T Cells

“…Lymphocyte homing to the liver is modulated by chemokines such as CXCR3 and CXCR6 ligands [21], [22]. Before transfer, NP-CTLs were mostly CXCR3 - and CXCR6 - (Figure 3 a and 4 a).…”

NOD2 Ligation Subverts IFN-α Production by Liver Plasmacytoid Dendritic Cells and Inhibits Their T Cell Allostimulatory Activity via B7-H1 Up-Regulation

“…Thus, the liver appears to play an important role in oral (50) and portal venous tolerance (51), whereas hepatic allografts are accepted more readily than others types of organ transplant (52–53), and can protect other grafts from the same donor from rejection (54–55). Furthermore, hepatitis B and C virus infection is more likely to induce chronic infection of the liver than other organs (56–57). Despite compelling evidence of hepatic tolerogenicity, the mechanisms that regulate the balance between tolerance and immunity in the liver microenvironment are still ill-defined.…”

Chemokines in the immunopathogenesis of hepatitis C infection #

“…Th1 immune responses dominate in the HCV infected liver30,63 and intrahepatic T cells express chemokine receptors associated with Th1 responses including CXCR3, CXCR6, CCR1 and CCR530,32,42,43. The distribution of chemokines within the liver compartmentalizes recruitment to different anatomical sites; CCR5 recruits lymphocytes to portal tracts whereas CXCR3 is essential for recruitment into the parenchyma via sinusoids and CXCR6 localizes cells to infected hepatocytes31,64–66 (figure 2 and 4).…”

“…CCR2 and CCR5 are characteristic of memory T cells5 and CD8 T cells expressing these receptors are enriched in the liver in HCV30,42,43. The receptors share chemokine ligands; CCR5 interacts with CCL3, CCL4, CCL5 and CCL8; and CCR2 interacts with CCL2, CCL13, CCL7 and CCL8 all of which have been detected in the liver30,80.…”