Sustained pre-TCR expression in Notch1IC-transgenic rats impairs T cell maturation and selection.
Notch1 is involved in directing cell fate decisions in a variety of developmental scenarios. Extending previous experiments in mice, we generated transgenic rats expressing the intracellular domain of Notch1 in the thymus. Importantly, this leads to sustained expression of the pre-TCR throughout thymocyte development, accompanied by a reduction of alphabetaTCR complexes. In addition, re-expression of RAG-1 and RAG-2 in TCRbeta(+) cells is impaired, and the Valpha repertoire is altered. Consequently, thymocytes in transgenic rats do not undergo positive selection and largely fail to progress to the single positive stage. According to our model, the previously reported effects of Notch1 on the CD4/CD8 cell fate decision may be explained by a differential sensitivity of the two lineages toward altered TCR signaling.
van den Brandt
Jens
J
Institute for Virology and Immunobiology, Molecular Immunology, University of Würzburg, Würzburg, Germany.
Kwon
Soon-Hwan
SH
Hünig
Thomas
T
McPherson
Kirsty G
KG
Reichardt
Holger M
HM
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; C497762:Notch1 protein, mouse; C497763:Notch1 protein, rat; C499308:Rag2 protein, mouse; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2; C090377:pre-T cell receptor alpha; C064658:RAG-1 protein