Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 26, Pages 10638-10643Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1019352108
Keywords
RNA; T-cell receptor rearrangement; allelic exclusion; B-cell receptor rearrangement; immune development
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Funding
- National Institutes of Health
- Howard Hughes Medical Institute
- Medical Scientist Training Program
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The random nature of T-cell receptor-beta (TCR-beta) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out-of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans-effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-beta, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous V beta-to-D beta J beta rearrangements, whereas D beta-to-J beta rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-beta rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-beta transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans-dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution.
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