Constitutive endocytosis and degradation of the pre-T cell receptor

Maddalena Panigada, Simona Porcellini, Eliane Barbier, Sonja Hoeflinger, Pierre André Cazenave, Hua Gu, Hamid Band, Harald Von Boehmer, Fabio Grassi

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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 γδTCR 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 γδTCR-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.

Original languageEnglish (US)
Pages (from-to)1585-1597
Number of pages13
JournalJournal of Experimental Medicine
Volume195
Issue number12
DOIs
StatePublished - Jun 17 2002
Externally publishedYes

Keywords

  • Pre-TCR
  • T cell development
  • Thymocyte
  • Ubiquitin
  • c-Cbl

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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