c-Cbl and Cbl-b Regulate T Cell Responsiveness by Promoting Ligand-Induced TCR Down-Modulation

Nat Immunol. 2002 Dec;3(12):1192-9. doi: 10.1038/ni855. Epub 2002 Nov 4.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cblb protein, mouse
  • Ligands
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Cbl protein, mouse

Associated data

  • GENBANK/X57111