Exit of the pre-TCR from the ER/cis-Golgi is necessary for signaling differentiation, proliferation, and allelic exclusion in immature thymocytes.
A major issue is whether surface expression of the pre-TCR is necessary for signaling the development of immature thymocytes. To address this question, we generated transgenic mice expressing a TCRbeta chain that had a strong endoplasmic reticulum (ER) retrieval signal (TCRbetaER) and that was expressed intracellularly but failed to reach the cell surface. In TCRbetaER transgenic mice, there was a failure of allelic exclusion. Also, the transgene failed to rescue the developmental defects observed in TCRbeta-null mice. In contrast, TCRbeta transgenes with a mutant ER retrieval sequence or lacking this sequence signaled efficient allelic exclusion and suppressed the TCRbeta-/- defect. These data show that exit of the pre-TCR from the ER/cis-Golgi is required for progression through the double-negative thymocyte checkpoint.
O'Shea
C C
CC
Imperial Cancer Research Fund, Lincoln's Inn Fields, London, United Kingdom.
Thornell
A P
AP
Rosewell
I R
IR
Hayes
B
B
Owen
M J
MJ
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
D016693:Receptors, Antigen, T-Cell, alpha-beta; D002118:Calcium