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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


  • Lineberry NB
  • Su LL
  • Lin JT
  • Coffey GP
  • Seroogy CM
  • Fathman CG


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

August 1, 2008

Associated Grants

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

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