Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion

Christine B.F. Thien, Frøydis D. Blystad, Yifan Zhan, Andrew M. Lew, Valentina Voigt, Christopher E. Andoniou, Wallace Y. Langdon

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57 Citations (Scopus)

Abstract

Signaling from the T-cell receptor (TCR) in thymocytes is negatively regulated by the RING finger-type ubiquitin ligase c-Cbl. To further investigate this regulation, we generated mice with a loss-of-function mutation in the c-Cbl RING finger domain. These mice exhibit complete thymic deletion by young adulthood, which is not caused by a developmental block, lack of progenitors or peripheral T-cell activation. Rather, this phenotype correlates with greatly increased expression of the CD5 and CD69 activation markers and increased sensitivity to anti-CD3-induced cell death. Thymic loss contrasts the normal fate of the c-Cbl-/- thymus, even though thymocytes from both mutant mice show equivalent enhancement in proximal TCR signaling, Erk activation and calcium mobilization. Remarkably, only the RING finger mutant thymocytes show prominent TCR-directed activation of Akt. We show that the mutant c-Cbl protein itself is essential for activating this pathway by recruiting the p85 regulatory subunit of PI 3-kinase. This study provides a unique model for analyzing high-intensity TCR signals that cause thymocyte deletion and highlights multiple roles of c-Cbl in regulating this process.

Original languageEnglish
Pages (from-to)3807-3819
Number of pages13
JournalThe EMBO Journal
Volume24
Issue number21
DOIs
Publication statusPublished - 2 Nov 2005

Keywords

  • Akt
  • Apoptosis
  • Cbl
  • CD3
  • Thymus

Cite this

Thien, C. B. F., Blystad, F. D., Zhan, Y., Lew, A. M., Voigt, V., Andoniou, C. E., & Langdon, W. Y. (2005). Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion. The EMBO Journal, 24(21), 3807-3819. https://doi.org/10.1038/sj.emboj.7600841