Taylor, A orcid.org/0000-0003-2295-2611, Harker, JA, Chanthong, K et al. (3 more authors) (2016) 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). pp. 274-286. ISSN 1074-7613
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Infection and Immunity (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Jul 2019 10:18 |
Last Modified: | 02 Jul 2019 19:12 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.immuni.2016.01.018 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:147973 |