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.
Naramura
Mayumi
M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Jang
Ihn-Kyung
IK
Kole
Hemanta
H
Huang
Fang
F
Haines
Diana
D
Gu
Hua
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D008024:Ligands; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C493849:Cbl protein, mouse