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Cutting edge: The transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy.

Activation of naive T lymphocytes is regulated through a series of discrete checkpoints that maintain unresponsiveness to self. During this multistep process, costimulatory interactions act as inducible signals that allow APCs to selectively mobilize T cells against foreign Ags. In this study, we provide evidence that the anergy-associated E3 ubiquitin ligase GRAIL (gene related to anergy in lymphocytes) regulates expression of the costimulatory molecule CD40L on CD4 T cells. Using its luminal protease-associated domain, GRAIL binds to the luminal/extracellular portion of CD40L and facilitates transfer of ubiquitin molecules from the intracellular GRAIL RING (really interesting new gene) finger to the small cytosolic portion of CD40L. Down-regulation of CD40L occurred following ectopic expression of GRAIL in naive T cells from CD40(-/-) mice, and expression of GRAIL in bone marrow chimeric mice was associated with diminished lymphoid follicle formation. These data provide a model for intrinsic T cell regulation of costimulatory molecules and a molecular framework for the initiation of clonal T cell anergy.

Pubmed ID: 18641297 RIS Download

Mesh terms: Animals | CD40 Ligand | Cell Differentiation | Cell Membrane | Cells, Cultured | Down-Regulation | Humans | Lymph Nodes | Mice | Mice, Inbred BALB C | Protein Binding | T-Lymphocytes | Ubiquitin-Protein Ligases | Ubiquitination | Up-Regulation

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Associated grants

  • Agency: NIAID NIH HHS, Id: U19 AI070352-030001
  • Agency: NIAID NIH HHS, Id: T32 AI007290
  • Agency: NIAID NIH HHS, Id: U19-AI070352
  • Agency: NIAID NIH HHS, Id: U19 AI070352
  • Agency: NCI NIH HHS, Id: R01 CA065237-17
  • Agency: NCI NIH HHS, Id: CA 65237-17
  • Agency: NIAID NIH HHS, Id: T32-AI07290-21
  • Agency: NCI NIH HHS, Id: R01 CA065237

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