CD3 epsilon recruits Numb to promote TCR degradation

Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3 epsilon that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3 epsilon chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.The work was funded by grants BFU2004-01771, BFU2007-67476 and BFU2010-21634 from the Spanish Science and Education Ministry, a Special Intramural CSIC (Spanish Science Council) grant and the Excellence grant P06-CTS-02112 from the Department of Science and Innovation of the Regional Government of Andalucia, Spain (M.C.), and grants SAF08-01581 and RD06/0020/0017 (J.L.).Peer reviewe