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c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation.

How Cbl family proteins regulate T cell responses is unclear. We found that c-Cbl Cbl-b double knock-out (dKO) T cells became hyperresponsive upon anti-CD3 stimulation, even though the major T cell antigen receptor (TCR) signaling pathways were not enhanced. The dKO T cells did not down-modulate surface TCR after ligand engagement, which resulted in sustained TCR signaling. However, these cells showed normal ligand-independent TCR internalization, and trafficking of internalized TCR to the lysosome compartment after ligand engagement was reduced. These findings show that Cbl family proteins negatively regulate T cell activation by promoting clearance of engaged TCR from the cell surface, a process that is apparently essential for the termination of TCR signals.

Pubmed ID: 12415267


  • Naramura M
  • Jang IK
  • Kole H
  • Huang F
  • Haines D
  • Gu H


Nature immunology

Publication Data

December 26, 2002

Associated Grants

  • Agency: NCI NIH HHS, Id: N01-CO-56000

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins
  • Down-Regulation
  • Ligands
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes
  • Ubiquitin-Protein Ligases