A role of calcineurin in coreceptor regulation during differentiation of Cd4Cd8 T cells

The immunosuppressant FK506 inhibits thymocyte positive selection. Calcineurin, a FK506-sensitive Ca super(2+)/calmodulin-dependent protein phosphatase, is presumed to be involved in this event without direct evidence. We have previously shown that moderate stimulation of CD4 super(+)CD8 super(+) thymocytes with a combination of the calcium ionophore ionomycin and phorbol myristate acetate mimics positive selection events including downregulation of CD8 expression. Moderate stimulation of a CD4 super(+)CD8 super(+) T cell line with the same combination of drugs also induced specific downregulation of CD8 expression. FK506 inhibited the CD8 downregulation in both cell types. The T cell line was transfected with an expression vector encoding an active form of calcineurin. The transfectans remained CD4 super(+)CD8 super(+), but became CD4 super(+)CD8 super(-) or CD4 super(+)CD8 super(low) upon stimulation with phorbol myristate acetate alone. The extent of the CD8 downregulation was correlated with the expression level of the mutant calcineurin. These results suggest that the calcium signal for the CD8 downregulation is mainly delivered through calcineurin activation.