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

Immunity. 2016 Feb 16;44(2):274-86. doi: 10.1016/j.immuni.2016.01.018.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / administration & dosage*
  • Aminophenols / adverse effects
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Herpesviridae Infections / immunology*
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / physiology*
  • Maleimides / administration & dosage*
  • Maleimides / adverse effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • RNA, Small Interfering / genetics
  • Rhadinovirus / physiology*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / virology
  • Viral Load / drug effects
  • Viral Load / genetics

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • Maleimides
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • RNA, Small Interfering
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Glycogen Synthase Kinase 3