CYCLOSPORINE-A INCREASES IFN-GAMMA PRODUCTION BY T-CELLS WHEN CO-STIMULATED THROUGH CD28

Despite its calcineurin-inhibiting properties, cyclosporin A (CsA) can not inhibit IL-2 production when T cells are co-stimulated by CD80/CD 86 on the antigen-presenting cells. We studied the in vitro effect of CsA on IFN-gamma production. Anti-CD3 monoclonal antibody (mAb) was us ed as the primary stimulus for activation of purified human T cells. A stimulating anti-CD28 mAb, or CD80 or CD86 on stably transfected P815 cells, provided the cc-stimulatory signal. IL-2 production was hardly affected by CsA under these stimulating conditions, while IFN-gamma ( at the protein and mRNA level) was markedly stimulated by CsA. The use of anti-CD3 or phorbol 12-myristate 13-acetate with ionomycin as the primary stimulus, together with costimulation through either CD28 or C D2 using transfectants with the appropriate ligands, allowed us to dem onstrate that the resistance of IFN-gamma production to inhibition by CsA required both CD3 and CD28 triggering. Inhibition of IL-10 product ion, and to a lesser degree of IL-4 production, by CD4(+) cells was re sponsible for the enhancement of IFN-gamma production in the presence of CsA. In conclusion, IFN-gamma production by CD28-co-stimulated CD4( +) T cells is resistant to inhibition by CsA and can even be facilitat ed by CsA as a result of removing a negative regulatory signal which i s mainly IL-10 mediated. This finding might have implications for immu nosuppressive strategies based upon the use of CsA.