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

Abstract

CD8 T cell killing of hepatitis C virus (HCV)-infected hepatocytes is thought to contribute to liver damage during chronic HCV infection, whereas the participation of HCV-nonspecific immune cells is unclear. To visualize the spatial relationship of HCV-specific CD8 T cells with parenchymal target cells, and to examine their local functional activity in relation to hepatocellular necrosis and fibrosis, we used HLA tetramers and confocal microscopy in biopsies from 23 HLA-A2 or HLA-B7 patients with chronic HCV infection. Intrahepatic tetramer؉ (HCV-specific) CD8 T cells protected from hepatic necroinflammatory disease activity, independently of age, gender, viral load, and viral genotype. Indeed, tetramer؉ cells were scattered in the liver within regions of weak fibrosis (low laminin expression) and low hepatocellular apoptosis (TUNEL method), and expressed IL-10 but not IFN␥. By contrast, tetramer-negative CD8 T cells were associated with active necroinflammatory liver disease, colocalized with strong laminin expression and hepatocellular apoptosis, and expressed more frequently IFN␥ than IL-10. Overall, liver regions harboring HCV-specific CD8 T cells tended to be healthier than areas containing only inflammatory cells of undefined specificity. In conclusion, HCV-specific IL-10-producing CD8 T cells, although not cytotoxic and unable to control viral replication, can attenuate hepatocellular necrosis, liver fibrosis, and inflammation mediated by bystander T cells, and may thus represent antigen-induced regulatory CD8 T cells. Therapeutic modulation of the intrahepatic balance between specific and bystander CD8 T cells might be beneficial in patients with chronic hepatitis C. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html).

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

“…24 Given that the HBV viral load was significantly higher in HBeAg ϩ individuals, we cannot exclude the possibility that a high HBV viral load or elevated ALT may be associated with increased IL-10 production in the liver and not HBeAg itself. In a larger cohort this could have been addressed with a multivariate analysis, but this was not possible here.…”

Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence

“…IL-10 levels are typically increased in chronic HCV infection (102). IL-10-producing T cells are preferentially located in areas of liver sections with low hepatocellular apoptosis and low laminin expression, whereas IFN-γ-producing T cells are localized to areas with strong hepatocellular apoptosis and laminin expression (103). IL-10-producing HCV-specific CD8 + T cells can be readily expanded from liver biopsies and suppress IFN-γ production and proliferation of virus-specific CD4 + and CD8 + T cells in vitro (104).…”

CD8+T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain

“…Impact of endogenous IL-10 on recovery from paclitaxel-induced mechanical allodynia CD8 ϩ T cells exert their regulatory effects in part through the production of anti-inflammatory cytokines such as IL-10 and TGF-␤ (Abel et al, 2006;Dai et al, 2010;Saraiva and O'Garra, 2010;Gabryšová et al, 2014;Kashi et al, 2014). We used neutralizing antibodies specific for IL-10 or TGF-␤ to examine the contribution of these anti-inflammatory cytokines to recovery from paclitaxel-induced mechanical allodynia in WT mice.…”