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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.
Golden-Mason, Lucy; Palmer, Brent E; Kassam, Nasim; Townshend-Bulson, Lisa; Livingston, Stephen; McMahon, Brian J; Castelblanco, Nicole; Kuchroo, Vijay; Gretch, David R; Rosen, Hugo R.
Afiliação
  • Golden-Mason L; Department of Medicine, University of Colorado Health Sciences Center and National Jewish Hospital, Denver, USA.
J Virol ; 83(18): 9122-30, 2009 Sep.
Article em En | MEDLINE | ID: mdl-19587053
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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Linfócitos T / Hepatite C / Proteínas de Membrana Limite: Adult / Aged / Humans / Middle aged Idioma: En Revista: J Virol Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Linfócitos T / Hepatite C / Proteínas de Membrana Limite: Adult / Aged / Humans / Middle aged Idioma: En Revista: J Virol Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos