Killing of immature CD4+ CD8+ thymocytes in vivo by anti-CD3 or 5'-(N-ethyl)-carboxamide adenosine is blocked by glucocorticoid receptor antagonist RU-486.
Negative selection in thymus occurs by apoptosis in CD4+CD8+ cells. These immature thymocytes are readily killed, both in vitro and in vivo, by glucocorticoid treatment. Increased levels of intracellular cAMP in vitro also induce apoptosis of thymocytes and T cell receptor (TcR) stimulation potentiate cAMP responses through receptors linked to adenylic cyclase. Presently, we have tested the possibility that TcR-mediated apoptosis in vivo may require the glucocorticoid receptor (GR) as a downstream, intracellular mediator. Use of the GR antagonist RU-486, 24 h before and simultaneous with, anti-CD3 or 5'-(N-ethyl)-carboxamide-adenosine (NECA) treatment, resulted in a selective inhibition of CD4+CD8+ thymocyte death. In addition, a low dose of glucocorticoid potentiated thymocyte death induced by anti-CD3 monoclonal antibodies. These data support a model in which thymic negative selection depends on a defined set of transduction signals which potentiate the GR to become responsive to endogenous levels of glucocorticoid.
Jondal
M
M
Department of Immunology, Karolinska Institutet, Stockholm, Sweden.
Okret
S
S
McConkey
D
D
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D003907:Dexamethasone / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D019830:Adenosine-5'-(N-ethylcarboxamide); D003907:Dexamethasone; D000241:Adenosine