Impaired fetal thymocyte development after efficient adenovirus-mediated inhibition of NF-kappa B activation.
We introduce a new experimental system combining adenovirus-mediated gene transfer and fetal thymic organ culture (FTOC). This system allowed us to efficiently express in developing thymocytes a mutant form of the NF-kappa B inhibitor I kappa B alpha (mut-I kappa B) and to study the maturation defects occurring when NF-kappa B activation is inhibited during fetal development. Fetal thymocytes infected with adenovirus containing mut-I kappa B were found to develop normally until the CD44-CD25+, CD4-CD8- double-negative stage, while production of more mature double-positive and single-positive populations was strongly decreased. Proliferation, as measured by the percentage of cells in cycle appeared normal, as did rearrangement and expression of the TCR beta-chain. However, apoptosis was much higher in FTOC infected with adenovirus containing mut-I kappa B than in FTOC infected with a control virus. Taken together, these results suggest that NF-kappa B plays a crucial role in ensuring the differentiation and survival of thymocytes in the early stages of their development.
Bakker
T R
TR
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Switzerland.
Renno
T
T
Jongeneel
C V
CV
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D020672:I-kappa B Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009924:Organ Culture Techniques; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D014162:Transfection / Q000276:immunology
D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2