Caspase enzyme activity is not essential for apoptosis during thymocyte development.
Caspases, a family of cysteine proteases, are critical mediators of apoptosis. To address the importance of caspases in thymocyte development, we have generated transgenic mice that express the baculovirus protein p35, a viral caspase inhibitor, specifically in the thymus. p35 expression inhibited Fas (CD95)-, CD3-, or peptide-induced caspase activity in vitro and conferred resistance to Fas-induced apoptosis. However, p35 did not block specific peptide-induced negative selection in OT1 and HY TCR transgenic mouse models. Even the potent pharmacological caspase inhibitor zVAD-FMK (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone) could not prevent peptide-induced deletion of OT1 thymocytes, although it improved basal thymocyte survival in vitro. Moreover, the developmental block observed in rag1-/- thymocytes, which lack pre-TCR signaling, was also not rescued by p35 expression. These results indicate that caspase-independent signal transduction pathways can mediate thymocyte death during normal T cell development.
Doerfler
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Department of Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065, USA. Petra_Doerfler@merck.com
Forbush
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KA
Perlmutter
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RM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology; D003433:Crosses, Genetic; D015853:Cysteine Proteinase Inhibitors / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017924:Nucleopolyhedroviruses / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006182:H-Y Antigen; D051034:Inhibitor of Apoptosis Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D010047:Ovalbumin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases