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Loss of c‐Cbl RING finger function results in high‐intensity TCR signaling and thymic deletion
Author(s) -
Thien Christine BF,
Blystad Frøydis D,
Zhan Yifan,
Lew Andrew M,
Voigt Valentina,
Andoniou Christopher E,
Langdon Wallace Y
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600841
Subject(s) - biology , t cell receptor , ring finger , microbiology and biotechnology , genetics , t cell , gene , immune system
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.