DIFFERENTIAL EFFECT OF RAPAMYCIN AND CYCLOSPORINE-A IN PROLIFERATION IN A MURINE T-CELL LINE EXPRESSING EITHER INTERMEDIATE OR HIGH-AFFINITY RECEPTOR FOR IL-2

It has been reported that rapamycin (rap), cyclosporin A (CsA) and FK5 06 have immunosuppressive effect during the activation process of muri ne T cells, These drugs were investigated for their suppressive effect on a murine T cell line expressing intermediate (TS1 beta) or high (T S1 alpha beta) affinity IL-2R. Rap and CsA strongly inhibit the IL-2-d ependent proliferation of TS1 alpha beta cells while they minimally af fect the IL-2-mediated proliferation of TS1 beta cells, FK506 does not have any effect on the IL-2-driven proliferation of either TS1 beta o r TS1 alpha beta cells. Simultaneous addition of Rap and CsA or Rap an d FK506 inhibit the IL-2-mediated proliferation of TS1 beta and TS1 al pha beta cells and therefore FK506 does not revert the inhibition medi ated by Rap in TS1 alpha beta cells, Neither Rap nor CsA affect IL-2R expression and internalization in TS lap cells, CsA and Rap strongly i nhibit the appearance of DNA binding activity of NF-AT and to a lesser extent NF-kappa B. Rap inhibits IL-2-stimulated phosphatidylinositol 3 (PI3) kinase activity in TS1 alpha beta cells, In TS1 beta cells, Ra p activates PI3 kinase on its own, inhibiting the IL-2-stimulated PI3 kinase to a lesser extent, These results suggest that PI3 kinase is a target for Rap action, Our results strongly suggest that we have Rap a nd CsA sensitive and resistant activation pathways operating in TS1 be ta and TS1 alpha beta cells.