Cyclosporin A inhibits the decrease of CD4/CD8 expression induced by protein kinase C activation

Cyclosporin A (CsA) is a powerful immunosuppressive drug widelyused in transplantation medicine. A major effect of CsA is inhibitionof the differentiation of immature double-positive (DP) CD4⁺CD8⁺thymocytes into mature single-positive (SP) CD4⁺CD8^– orCD4^–CD8⁺thymocytes. The mechanisms underlying the changesin CD4/CD8 expression during normal differentiation of thymocytesand the way CsA interferes with this differentiation processare still unknown. Here we show that protein kinase C (PKC)activation by phorbol 12-myristate 13-acetate (PMA) causes adecrease of both CD4 and CD8 expression at the cell surfacelevel and at the mRNA level in a CD4⁺CD8⁺ T cell line and infreshly isolated thymocytes. A PKC inhibitor, staurosporin,interferes with the differentiation from DP to SP in fetal thymusorgan culture system. These data suggest that the alternationof CD4/CD8 expression from DP to SP is dependent on PKC activation.CsA blocks this decrease of CD4/CD8 expression by PMA in vitro.Moreover, this PMA effect is also blocked by treatment withcycloheximlde. These results suggest that the reduction of CD4/CD8expression requires de novo synthesis of a protein(s) inducedin response to a signal conveyed by activated PKC. CsA may blockthe transition from DP to SP by inhibition of CD4/CD8 down-regulationinduced by PKC activation.