Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells.
A number of emerging molecules and pathways have been implicated in mediating the T-cell exhaustion characteristic of chronic viral infection. Not all dysfunctional T cells express PD-1, nor are they all rescued by blockade of the PD-1/PD-1 ligand pathway. In this study, we characterize the expression of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) in chronic hepatitis C infection. For the first time, we found that Tim-3 expression is increased on CD4(+) and CD8(+) T cells in chronic hepatitis C virus (HCV) infection. The proportion of dually PD-1/Tim-3-expressing cells is greatest in liver-resident T cells, significantly more so in HCV-specific than in cytomegalovirus-specific cytotoxic T lymphocytes. Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127(low) CD57(high)), a central rather than effector memory profile (CD45RA(negative) CCR7(high)), and reduced Th1/Tc1 cytokine production. We also demonstrate the ability to enhance T-cell proliferation and gamma interferon production in response to HCV-specific antigens by blocking the Tim-3-Tim-3 ligand interaction. These findings have implications for the development of novel immunotherapeutic approaches to this common viral infection.
Golden-Mason
Lucy
L
Department of Medicine, University of Colorado Health Sciences Center and National Jewish Hospital, Denver, USA.
Palmer
Brent E
BE
Kassam
Nasim
N
Townshend-Bulson
Lisa
L
Livingston
Stephen
S
McMahon
Brian J
BJ
Castelblanco
Nicole
N
Kuchroo
Vijay
V
Gretch
David R
DR
Rosen
Hugo R
HR
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D000072597:Hepatitis A Virus Cellular Receptor 2; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult
D015703:Antigens, CD; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins