Dexamethasone enhances CTLA-4 expression during T cell activation

• Published in: Cellular and molecular life sciences : CMLS 1999-09, Vol.55 (12), p.1649-1656
• Main Authors: Xia, M, Gasser, J, Feige, U
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; Anti-Inflammatory Agents - pharmacology; Antigen presentation; Antigens, CD; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - immunology; CD28 Antigens - immunology; Cells, Cultured; CTLA-4 Antigen; CTLA-4 protein; Cytokines; dexamethasone; Dexamethasone - pharmacology; Immunoconjugates; Kinetics; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Proteins; Rodents; Steroids; T cell receptors; T-Lymphocytes - immunology
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s000180050403

T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2. CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4 is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10(-8) M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4 expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28 mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.