The influence of cyclosporin A on the alternative pathways of human T cell activation in vitro.
To gain further insight into the mechanism of action of the immunosuppressant cyclosporin A (CyA), we investigated the influence of CyA on proliferative responses of human T lymphocytes, induced via different membrane molecules. As was previously shown, activation of T cells via the T cell receptor (Ti)/CD3 complex with an anti-CD3 monoclonal antibody was inhibited by CyA. Likewise, triggering of T lymphocytes via the alternative, CD2(T11)-mediated pathway of activation was strongly inhibited. In contrast, responses induced by phorbol myristate 13-acetate (PMA; 100 ng/ml) or the combination of an anti-CD28 monoclonal antibody and a suboptimal concentration of PMA (1 ng/ml) were found to be insensitive to CyA. CyA-induced inhibition of both anti-CD3- and anti-CD2-mediated proliferation could not be reversed by addition of either PMA (1 ng/ml) or anti-CD28. An increase in the intracellular free Ca2+ concentration [( Ca2+]i) is an early event observed after stimulation of T cells via CD3 or CD2, whereas stimulation with PMA and anti-CD28 does not lead to a rise in [Ca2+]i. This suggests that the inhibitory action of CyA is related to Ca2+-dependent signaling pathways. Since we observed that CyA does not interfere with anti-CD3- or anti-CD2-induced increases of [Ca2+]i, our data suggest that CyA-mediated inhibition is related to a later event in these intracellular signaling pathways.
Bloemena
E
E
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam.
Van Oers
R H
RH
Weinreich
S
S
Stilma-Meinesz
A P
AP
Schellekens
P T
PT
Van Lier
R A
RA
D000911:Antibodies, Monoclonal / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D003524:Cyclosporins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D002118:Calcium