Bidirectional effects of corticosterone on splenic T-cell activation: critical role of cell density and culture time.
Glucocorticoids inhibit stimulus-induced T-cell proliferation, an early and essential parameter of cellular immunity. It was recently found however that physiological concentrations of glucocorticoids can also accelerate, not only inhibit, rat T-cell mitogenesis. We investigated mechanism(s) underlying mitogenic actions of glucocorticoids on anti-T-cell receptor (TCR)- and concanavalin A (Con A)-induced T-cell proliferation. Surprisingly, the ability of the glucocorticoid corticosterone (CORT) to either enhance or inhibit T-cell proliferation was found to depend primarily on the cell density and the timing of the cultures. At cell densities up to 1 x 10(5) cells/well (i.e. 'low' density), CORT inhibited T-cell proliferation irrespective of the culture time. In contrast, at cell densities of 2 x 10(5) cells/well and higher ('high' density), CORT potently stimulated T-cell mitogenesis during the first 2-3 culture days, but subsequently inhibited the proliferative response after 5-7 days. The glucocorticoid receptor antagonist RU486 completely abolished the effects of CORT. However, production of the main T cell growth factor interleukin (IL)-2 was inhibited by CORT at both 'low' and 'high' cell densities. In addition, irrespective of cell density, T-cell mitogenesis under either control conditions or in presence of CORT was completely blocked by an anti-IL-2-receptor-alpha-chain (IL-2Ralpha) antibody, indicating that T-cell proliferation was dependent on the IL-2 pathway. Immunofluorescence staining of IL-2Ralpha on CD4+ cells after 2-3 days in culture was increased by CORT, but only on cells cultured at 'high' density. Thus, glucocorticoids increase T-cell responsiveness to IL-2 under conditions of 'high' cell density only. We conclude that glucocorticoids may contribute to a more efficient early stage of cellular immune responses under conditions of intimate cell-to-cell contact (i.e. 'high' cell density), a situation likely to be present in vivo, for instance in lymph nodes. Thus, these findings are relevant to our understanding of the glucocorticoid control of immune function.
Wiegers
G J
GJ
Max Planck Institute of Psychiatry, Section of Neuropsychopharmacology, Munich, Germany.
Stec
I E
IE
Klinkert
W E
WE
Linthorst
A C
AC
Reul
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002452:Cell Count; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000166:cytology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003208:Concanavalin A; D003345:Corticosterone