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.