Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation

J Immunol. 2017 Dec 15;199(12):4056-4065. doi: 10.4049/jimmunol.1600396. Epub 2017 Nov 6.

Abstract

The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K-protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity. In this study, we further examined the molecular pathway linking PKB and Cbl-b in murine models. Our data show that the protein kinase GSK-3, one of the first targets identified for PKB, catalyzes two previously unreported phosphorylation events at Ser476 and Ser480 of Cbl-b. GSK-3 inactivation by PKB abrogates phosphorylation of Cbl-b at these two sites and results in reduced Cbl-b protein levels. We further show that constitutive activation of PKB in vivo results in a loss of tolerance that is mediated through the downregulation of Cbl-b. Altogether, these data indicate that the PI3K-PKB-GSK-3 pathway is a novel regulatory axis that is important for controlling the decision between T cell activation and tolerance via Cbl-b.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Autoimmunity / physiology
  • Enzyme Activation
  • Gene Expression Regulation / immunology
  • Glycogen Synthase Kinase 3 / physiology*
  • Immune Tolerance / physiology*
  • Lymphocyte Activation / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Sequence Alignment
  • Signal Transduction / physiology
  • Species Specificity
  • Specific Pathogen-Free Organisms
  • T-Lymphocyte Subsets / enzymology*
  • T-Lymphocyte Subsets / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Cblb protein, mouse
  • Protein Isoforms
  • Phosphoserine
  • Proto-Oncogene Proteins c-cbl
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3

Grant support