SummaryDespite 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.
Graphical Abstract Highlights d Glycogen synthase kinase-3 regulates the transcription of LAG-3 on CD4 and CD8 T cells d Small molecule inhibitors (SMIs) of GSK-3 selectively downregulated LAG-3 and PD-1 d GSK-3 inhibition acted by upregulating the transcription factor Tbet d Combining GSK-3 SMIs with anti-LAG-3 Ab is more effective than either alone
Highlights d Glycogen synthase kinase-3 regulates the transcription of LAG-3 on CD4 and CD8 T cells d Small molecule inhibitors (SMIs) of GSK-3 selectively downregulated LAG-3 and PD-1 d GSK-3 inhibition acted by upregulating the transcription factor Tbet d Combining GSK-3
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