Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction

Immunity. 2004 Aug;21(2):167-77. doi: 10.1016/j.immuni.2004.07.013.


Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adoptive Transfer
  • Animals
  • Antigens / immunology
  • Clonal Anergy / immunology*
  • Clonal Anergy / physiology
  • Enterotoxins / immunology
  • In Vitro Techniques
  • Mice
  • Phospholipase C gamma
  • Proto-Oncogene Proteins c-cbl
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Type C Phospholipases / metabolism
  • Ubiquitin-Protein Ligases / immunology
  • Ubiquitin-Protein Ligases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antigens
  • Cblb protein, mouse
  • Enterotoxins
  • enterotoxin B, staphylococcal
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Type C Phospholipases
  • Phospholipase C gamma