Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappaB/Rel.
Signaling from the TCR regulates T lymphoid survival, deletion by apoptosis, and selective clonal expansion. One set of signaling pathways activated during thymic selection leads to degradation of a cytosolic retention protein, the inhibitor of kappaB (IkappaB)alpha, followed by nuclear translocation of the NF-kappaB/Rel family of transcription factors. It has been found previously that NF-kappaB proteins mediate a pathway signaling the survival of mature T cells and protection of thymocytes against TNF-induced apoptosis. In contrast, we show in this study that a transgenic inhibitor of NF-kappaB/Rel signaling interferes with the negative selection of immature thymocytes by endogenous MHC ligands in vivo. Positive selection of the H-Y TCR also was diminished. This attenuation of thymic selection efficiency was associated with decreased ZAP-70 phosphorylation and TCR signaling of CD69 induction. These findings demonstrate that the NF-kappaB transcriptional pathway plays an important role in normal processes of clonal deletion and they indicate that the NF-kappaB/IkappaB axis can regulate the efficiency of TCR signaling.
Mora
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AL
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Stanley
S
S
Armistead
W
W
Chan
A C
AC
Boothby
M
M
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D017637:Clonal Deletion; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020672:I-kappa B Proteins; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D000072000:NF-KappaB Inhibitor alpha; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse