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 β) 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.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminophenols / administration & dosage*
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Aminophenols / adverse effects
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / virology
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Cells, Cultured
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Cytotoxicity, Immunologic / drug effects
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Cytotoxicity, Immunologic / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Herpesviridae Infections / immunology*
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Lymphocytic Choriomeningitis / immunology*
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Lymphocytic choriomeningitis virus / physiology*
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Maleimides / administration & dosage*
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Maleimides / adverse effects
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / metabolism*
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RNA, Small Interfering / genetics
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Rhadinovirus / physiology*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism*
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / virology
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Viral Load / drug effects
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Viral Load / genetics
Substances
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3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
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Aminophenols
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Maleimides
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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RNA, Small Interfering
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Glycogen Synthase Kinase 3