title: Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses.
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.
authors.affiliation: Cell Signalling Section, Division of Immunology, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Harker
authors.affiliation: Cell Signalling Section, Division of Immunology, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Kittiphat
authors.initials: K
authors.lastname: Chanthong
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Elina I
authors.initials: EI
authors.lastname: Zuniga
authors.affiliation: Cell Signalling Section, Division of Immunology, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK. Electronic address: cer51@cam.ac.uk.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D008301:Maleimides / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018144:Rhadinovirus / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D019562:Viral Load / Q000187:drug effects / Q000235:genetics; D000098815:T-bet Transcription Factor
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D038362:Glycogen Synthase Kinase 3