GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells

Immunity. 2003 Apr;18(4):535-47. doi: 10.1016/s1074-7613(03)00084-0.


T cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4(+) T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Calcineurin / physiology
  • Cell Line
  • Cytokines / genetics*
  • Endocytosis
  • Humans
  • Immune Tolerance*
  • Interleukin-2 / biosynthesis
  • Ionomycin / pharmacology
  • Ligases / chemistry
  • Ligases / physiology*
  • Molecular Sequence Data
  • Transcription, Genetic*
  • Transferrin / metabolism
  • Ubiquitin-Protein Ligases
  • Zinc / metabolism


  • Cytokines
  • Interleukin-2
  • Transferrin
  • Ionomycin
  • Ubiquitin-Protein Ligases
  • Calcineurin
  • Ligases
  • Zinc