Hepatic iNKT cells produce type 2 cytokines and restrain antiviral T cells during acute hepacivirus infection

Abstract

Chronic hepatitis C virus (HCV) infection is a curable disease, but the absence of a vaccine remains a major problem in infection prevention. The lack of small animal models and limited access to human liver tissue impede the study of hepatic antiviral immunity and the development of new vaccine strategies. We recently developed an immune-competent mouse model using an HCV-related rodent hepacivirus which shares immunological features with human viral hepatitis. In this study, we used this new model to investigate the role of invariant natural killer T (iNKT) cells during hepacivirus infection in vivo. These cells are enriched in the liver, however their role in viral hepatitis is not well defined. Using high-dimensional flow cytometry and NKT cell deficient mice we analyzed a potential role of iNKT cells in mediating viral clearance, liver pathology or immune-regulation during hepacivirus infection. In addition, we identified new immune-dominant MHC class I restricted viral epitopes and analyzed the impact of iNKT cells on virus-specific CD8+ T cells. We found that rodent hepacivirus infection induced the activation of iNKT cell subsets with a mixed NKT1/NKT2 signature and significant production of type 2 cytokines (IL-4 and IL-13) during acute infection. While iNKT cells were dispensable for viral clearance, the lack of these cells caused higher levels of liver injury during infection. In addition, the absence of iNKT cells resulted in increased effector functions of hepatic antiviral T cells. In conclusion, our study reports a regulatory role of hepatic iNKT cells during hepacivirus infection in vivo. Specifically, our data suggest that iNKT cells skewed towards type 2 immunity limit liver injury during acute infection by mechanisms that include the regulation of effector functions of virus-specific T cells.

The role of natural killer T cells in liver transplantation

“…This can occur either through direct secretion of IL-10 or by influencing other IL-10 producing cells, such as Treg cells. Raus S has developed an HCV related rodent hepatitis virus (NrHV), which was isolated from Norwegian rats (Raus et al, 2022). They found that in the models of NrHV infection in CD1d −/− mice with iNKT deficiency and normal mice, the levels of ALT were significantly increased in the iNKT-deficient mice after infection.…”

“…Accordingly, iNKT cells that are biased towards type 2 immunity play a limiting role in acute liver injury during infection. This is achieved through direct or indirect means, including the regulation of antiviral effector functions of T cells that are specific to the virus (Raus et al, 2022). However, their effect on hepatic cells is dual in nature and could be attributed to the distinct roles played by their subgroups.…”

“…However, their effect on hepatic cells is dual in nature and could be attributed to the distinct roles played by their subgroups. Certain research indicates that during particular immune response mechanisms, diverse immune microenvironments within the liver shape the function and polarization of iNKT cells (Raus et al, 2022).…”

Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment

“…Furthermore, recent evaluations of blood from patients with acute HCV showed that iNKT cells may be associated with acute liver damage [ 116 ]. However, using the NrHV mouse model has allowed for a more in-depth investigation of the role of hepatic iNKT cells [ 117 ]. This work suggested that hepatic IL-4 and IL-13 secreting iNKT cells may limit rather than enhance liver damage by suppressing the antiviral T cell responses [ 117 ].…”

“…However, using the NrHV mouse model has allowed for a more in-depth investigation of the role of hepatic iNKT cells [ 117 ]. This work suggested that hepatic IL-4 and IL-13 secreting iNKT cells may limit rather than enhance liver damage by suppressing the antiviral T cell responses [ 117 ]. Thus, functionally distinct iNKT cell subsets might be active in blood and liver during different stages of acute infection [ 116 , 117 ].…”