Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions

J Immunol. 2011 Feb 15;186(4):2138-47. doi: 10.4049/jimmunol.1003390. Epub 2011 Jan 19.


E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic E3 ligase activity. The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo. Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Cell Line, Tumor
  • Clonal Anergy / genetics
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Female
  • Gene Knock-In Techniques
  • Immunophenotyping
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Point Mutation
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / physiology*
  • RING Finger Domains / genetics
  • T-Lymphocyte Subsets / enzymology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Cytotoxic / enzymology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / pathology
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*


  • Adaptor Proteins, Signal Transducing
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases