Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo.
Poly- and oligoclonal T cell stimuli like anti-CD3 epsilon monoclonal antibody or Staphylococcus aureus enterotoxin B (SEB), injected at doses that per se are not lethal, provoke acute death within less than 24 h, provided that endogenous glucocorticoids (GC) are depleted by adrenalectomy or by injection of saturating amounts of the GC receptor antagonist RU-38486 (mifepristone). Pharmacological doses of the GC agonist dexamethasone (DEX) alter the in vivo response of splenic V beta 8+ T cells to SEB, thus impeding the expansion of such cells and causing their rapid (3 d) clonal deletion. In contrast, coadministration of RU-38486 counteracts a SEB-induced early (12 h) reduction of V beta 8+CD4+ and V beta 8+CD8+ spleen cells. In vivo T cell stimulation by injection of bacterial superantigen induces a rapid (peak at 90-120 min) increase in corticosterone serum levels, suggesting that endogenous GC might control early T cell activation. Accordingly, kinetic studies revealed that RU-38486 has to be administered within 2 h after superantigen administration to exert its lethal effect. Similarly, exogenous GC must be injected during this critical phase (2 h) to rescue animals from acute death induced by coinjection of SEB and D-galactosamine (GalN). Adrenalectomy, injection of RU-38486 and priming with GalN per se provoke the programmed death of peripheral CD4+ and CD8+ T cells. Thus, three manipulations that sensitize mice for the lethal effect of T cell stimulation also exert a proapoptotic effect on peripheral T cells. In synthesis, endogenous and exogenous GC regulate T cell responses and determine the propensity of peripheral T cells to undergo apoptosis.
Gonzalo
J A
JA
Centro de Biología Molecular (Consejo Superior de Investigaciones Científicas), Universidad Autónoma de Madrid, Spain.
González-García
A
A
Martínez
C
C
Kroemer
G
G
D000818:Animals; D000941:Antigens / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D005938:Glucocorticoids / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013211:Staphylococcus aureus / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D000941:Antigens; D004768:Enterotoxins; D005938:Glucocorticoids; D015735:Mifepristone; C031818:enterotoxin B, staphylococcal; D003907:Dexamethasone