Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses.
Immunity
; 44(2): 274-86, 2016 Feb 16.
Article
em En
| MEDLINE
| ID: mdl-26885856
ABSTRACT
Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and ß) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8(+) T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T Citotóxicos
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Rhadinovirus
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Infecções por Herpesviridae
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Linfócitos T CD8-Positivos
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Proteínas com Domínio T
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Quinase 3 da Glicogênio Sintase
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Receptor de Morte Celular Programada 1
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Aminofenóis
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Coriomeningite Linfocítica
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Vírus da Coriomeningite Linfocítica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Immunity
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido