Role of DNA fragmentation in T cell activation-induced apoptosis in vitro and in vivo.
Apoptotic cell death, characterized by DNA fragmentation and morphologic changes, has previously been shown to occur in immature thymocytes and some T cell hybridomas after activation. Like some other forms of apoptosis, DNA fragmentation during activation-induced cell death precedes the morphologic events. For apoptosis to proceed, activation of the cells must persist at least to the time of DNA fragmentation, before which the cells can remain viable if the activation signal is removed. Aurintricarboxylic acid (ATA) blocks activation-induced apoptotic cell death in a T cell hybridoma, and kinetic studies show that this inhibition occurs at or near the time of DNA fragmentation in the cells. Taken together with the ability of ATA to inhibit DNA fragmentation in isolated nuclei exposed to Ca2+ and Mg2+, these data strongly suggest that ATA prevents apoptosis via its ability to inhibit endogenous endonuclease activity, and, conversely, that this activity is required for this form of cell death. In vivo, ATA inhibits thymocyte depletion and DNA fragmentation induced by anti-CD3 Ab. Further, specific loss of V beta 8+ thymocytes after administration of staphylococcal enterotoxin B is blocked by administration of ATA. These observations support an essential role for DNA fragmentation as an irreversible step in activation-induced apoptosis in T cell hybridomas and during T cell development. This is contrasted with heat shock-induced cell death, in which inhibition of DNA fragmentation does not prevent loss of cell viability.
Mogil
R J
RJ
La Jolla Institute for Allergy and Immunology, CA 92037.
Shi
Y
Y
Bissonnette
R P
RP
Bromley
P
P
Yamaguchi
I
I
Green
D R
DR
D000818:Animals; D017209:Apoptosis; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D006358:Hot Temperature; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*
D001312:Aurintricarboxylic Acid; D004247:DNA