Upregulation of the Tim-3/Galectin-9 Pathway of T Cell Exhaustion in Chronic Hepatitis B Virus Infection

Abstract

The S-type lectin galectin-9 binds to the negative regulatory molecule Tim-3 on T cells and induces their apoptotic deletion or functional inactivation. We investigated whether galectin-9/Tim-3 interactions contribute to the deletion and exhaustion of the antiviral T cell response in chronic hepatitis B virus infection (CHB). We found Tim-3 to be expressed on a higher percentage of CD4 and CD8 T cells from patients with CHB than healthy controls (p<0.0001) and to be enriched on activated T cells and those infiltrating the HBV-infected liver. Direct ex vivo examination of virus-specific CD8 T cells binding HLA-A2/peptide multimers revealed that Tim-3 was more highly upregulated on HBV-specific CD8 T cells than CMV-specific CD8 T cells or the global CD8 T cell population in patients with CHB (p<0.001) or than on HBV-specific CD8 after resolution of infection. T cells expressing Tim-3 had an impaired ability to produce IFN-γ and TNF-α upon recognition of HBV-peptides and were susceptible to galectin-9-triggered cell death in vitro. Galectin-9 was detectable at increased concentrations in the sera of patients with active CHB-related liver inflammation (p = 0.02) and was strongly expressed by Kupffer cells within the liver sinusoidal network. Tim-3 blockade resulted in enhanced expansion of HBV-specific CD8 T cells able to produce cytokines and mediate cytotoxicity in vitro. Blocking PD-1 in combination with Tim-3 enhanced the number of patients from whom functional antiviral responses could be recovered and/or the strength of responses, indicating that these co-inhibitory molecules play a non-redundant role in driving T cell exhaustion in CHB. Patients taking antivirals able to potently suppress HBV viraemia continued to express Tim-3 on their T cells and respond to Tim-3 blockade. In summary, both Tim-3 and galectin-9 are increased in CHB and may contribute to the inhibition and deletion of T cells as they infiltrate the HBV-infected liver.

Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada

“…Acute HBV infection is highly self-limiting, described as elimination of HBsAg from the blood within 6 months [17]. Resolution of an acute HBV infection leaves the host with lifelong protection.…”

“…However, due to the virus' replicative nature, the host is not cleared of HBV when resolution is achieved; HBV is merely controlled by the host immune system much like a latent infection. Therefore, future reactivation is possible during host immunosuppression [17].…”

Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

“…LSECtin deficiency does not affect the expression of programmed cell death ligand-1 and Galectin-9 in the liver It is noteworthy that the suppressive molecules programmed cell death ligand-1 (PD-L1) and Galectin-9 are expressed in the liver and that these molecules play crucial roles in the regulation of T cell immunity during viral infection in the liver (22)(23)(24). Therefore, we evaluated the expression of PD-L1 and Galectin-9 on the LSECs and Kupffer cells of LSECtin 2/2 mice.…”

Kupffer Cells Support Hepatitis B Virus–Mediated CD8+ T Cell Exhaustion via Hepatitis B Core Antigen–TLR2 Interactions in Mice

“…We proved that KCs play an important role in inhibiting Ab production in HBVpersistent mice because, following KC depletion, the hepatitis B surface Ab (anti-HBs) recall response in HBV-carrier mice after hepatitis B surface Ag (HBsAg) vaccination could be reconstituted (11). In addition, KCs might induce T cell exhaustion by upregulating galectin-9 expression in patients with chronic HBV infection and in patients with HBV-associated hepatocellular carcinoma (12,13). However, until now, the roles of most other molecules expressed on KCs in the induction of T cell exhaustion have remained unreported.…”