Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8 ⁺ Cytolytic T Cell Responses

Summary

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.

Graphical Abstract

Highlights

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  GSK-3 is a key upstream kinase that contributes to inhibition of PD-1 transcription

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  GSK-3 siRNAs or inhibitors block PD-1 transcription to thereby enhance CTL function

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  GSK-3 inhibition enhances Tbx21 transcription, which represses PD-1 transcription

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  Use of GSK-3 inhibitors in vivo downregulates PD-1 and enhances viral clearance

Abstract

The upstream pathway regulating PD-1 expression is not clear. Rudd and colleagues show that inhibition of the serine/threonine kinase GSK-3 upregulates T-bet expression, which decreases PD-1 expression and enhances CTL function. They demonstrate that the use of GSK-3 inhibitors in vivo inhibits PD-1 and enhances T cell clearance of viral infections.