Synergy between T cell Receptor and Fas (CD95/APO-1) signaling in mouse thymocyte death.
Administration of anti-TCR/CD3epsilon antibody in vivo or in thymic organ culture results in the apoptotic death of CD4+/CD8+ thymocytes. In contrast, purified thymocytes in suspension culture are resistant to TCR/CD3epsilon-induced apoptotic death. We show that induction of thymocyte death, in suspension culture, can be induced by the combination of TCR/CD3epsilon and Fas (CD95/Apo-1) signaling. No significant thymocyte death was observed after in vitro Fas cross-linking unless TCR/CD3epsilon was simultaneously co-cross-linked or metabolic inhibitors such as actinomycin D were added. Furthermore, TCR/CD3epsilon and Fas synergy did not operate through upregulation of Fas but by facilitation of the Fas-mediated death signal. Both TCRmid/lo/HSAhi/CD4+/CD8+ (double positive) and TCRhi/HSAlo/CD4+/CD8- or CD4-/CD8+ (single positive) thymocytes were susceptible to death induced by co-cross-linking of TCR/CD3epsilon and Fas. Our results reveal a signaling synergy between the Fas and TCR/CD3epsilon complex that has important implications for our understanding of in vivo vs in vitro models of thymocyte deletion.
Fisher
G H
GH
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Lenardo
M J
MJ
Zuniga-Pflucker
J C
JC
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor