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Constitutive Endocytosis and Degradation of the Pre-T Cell Receptor

Maddalena Panigada¹, Simona Porcellini¹, Eliane Barbier², Sonja Hoeflinger⁴, Pierre-André Cazenave^2,3, 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 p56^lck, actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the 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 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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