Tonic ubiquitylation controls T-cell receptor: CD3 complex expression during T-cell development

Haopeng Wang, Jeff Holst, Seng Ryong Woo, Cliff Guy, Matt Bettini, Yao Wang, Aaron Shafer, Mayumi Naramura, Michaël Mingueneau, Leonard L. Dragone, Sandra M. Hayes, Bernard Malissen, Hamid Band, Dario A A Vignali

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Expression of the T-cell receptor (TCR):CD3 complex is tightly regulated during T-cell development. The mechanism and physiological role of this regulation are unclear. Here, we show that the TCR:CD3 complex is constitutively ubiquitylated in immature double positive (DP) thymocytes, but not mature single positive (SP) thymocytes or splenic T cells. This steady state, tonic CD3 monoubiquitylation is mediated by the CD3 proline-rich sequence, Lck, c-Cbl, and SLAP, which collectively trigger the dynamin-dependent downmodulation, lysosomal sequestration and degradation of surface TCR:CD3 complexes. Blocking this tonic ubiquitylation by mutating all the lysines in the CD3 cytoplasmic tails significantly upregulates TCR levels on DP thymocytes. Mimicking monoubiquitylation by expression of a CD3-monoubiquitin (monoUb) fusion molecule significantly reduces TCR levels on immature thymocytes. Moreover, modulating CD3 ubiquitylation alters immunological synapse (IS) formation and Erk phosphorylation, thereby shifting the signalling threshold for positive and negative selection, and regulatory T-cell development. Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T-cell development.

Original languageEnglish (US)
Pages (from-to)1285-1298
Number of pages14
JournalEMBO Journal
Volume29
Issue number7
DOIs
Publication statusPublished - Apr 1 2010

    Fingerprint

Keywords

  • C-Cbl
  • Signalling
  • T-cell development
  • T-cell receptor:CD3
  • Ubiquitylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Wang, H., Holst, J., Woo, S. R., Guy, C., Bettini, M., Wang, Y., ... Vignali, D. A. A. (2010). Tonic ubiquitylation controls T-cell receptor: CD3 complex expression during T-cell development. EMBO Journal, 29(7), 1285-1298. https://doi.org/10.1038/emboj.2010.10