The Journal of Experimental Medicine
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Published online 10 June 2002 doi:10.1084/jem.20020047
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© Rockefeller University Press, 0022-1007/2002/6/1585/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 12, June 17, 2002 1585-1597
Constitutive Endocytosis and Degradation of the Pre-T Cell Receptor

Maddalena Panigada1, Simona Porcellini1, Eliane Barbier2, Sonja Hoeflinger4, Pierre-André Cazenave2,3, Hua Gu6, Hamid Band5, Harald von Boehmer4 and Fabio Grassi4

1 Dipartimento di Biologia e Genetica per le Scienze Mediche, Università degli Studi di Milano, 20133 Milano, Italy
2 Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France
3 Université Pierre et Marie Curie (Paris 6), 75005 Paris, France
4 Department of Pathology, Dana Farber Cancer Institute
5 Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
6 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Address correspondence to Fabio Grassi, Dana Farber Cancer Institute, 1 Jimmy Fund Way, Boston, MA 02115. Phone: 617-632-6885; Fax: 617-632-6881; E-mail: fabio_grassi{at}dfci.harvard.edu

The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56lck, actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the {gamma}{delta}TCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR– but not {gamma}{delta}TCR-expressing cells. A role of c-Cbl–mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl–deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function.

Key Words: c-Cbl • pre-TCR • T cell development • thymocyte • ubiquitin


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