Nature Immunology
3, 1192 - 1199 (2002)
Published online: 4 November 2002; | doi:10.1038/ni855
c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulationMayumi Naramura1, 3, 4, Ihn-Kyung Jang1, 4, Hemanta Kole1, 4, Fang Huang1, Diana Haines2
& Hua Gu11
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA. 2
Pathology/Histotechnology Laboratory, National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, MD 21702, USA. 3
Present address: Department of Immunology, Cleveland Clinic Foundation, NB-30, 9500 Euclid Avenue, Cleveland, OH 44195, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Hua Gu hgu@niaid.nih.govHow 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.
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