title: 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.
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Gaia
authors.initials: G
authors.lastname: Nebbia
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Pooja
authors.initials: P
authors.lastname: Khanna
authors.forename: Harsimran D
authors.initials: HD
authors.lastname: Singh
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: William
authors.initials: W
authors.lastname: Rosenberg
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dusheiko
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.forename: Joanne
authors.initials: J
authors.lastname: ChinAleong
authors.forename: Patrick
authors.initials: P
authors.lastname: Kennedy
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D037161:Galectins / Q000235:genetics* / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000276:immunology / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins