Yeast as model T cells

Abstract

The immunosuppressants cyclosporin A, FK-506, and rapamycin prevent T-cell activation by inhibiting intermediate signal transduction steps. Studies have focused on their mechanisms of action, with the aim of both designing novel immunosuppressants and understanding signal transduction. Biochemical studies first identified the primary drug targets, the immunophilins cyclophilin and FKBP. Genetic studies in yeast demonstrated that the active agents in vivo are toxic protein-drug complexes. The target of cyclophilin-CsA and FKBP12-FK-506, the calcium- and calmodulin-regulated phosphatase calcineurin, regulates nuclear import of a T-cell-specific transcription factor during response to antigen. In yeast, calcineurin is required for recovery from pheromone-induced cell cycle arrest. The challenges ahead are to understand the normal cellular roles of the immunophilins, to biochemically define the direct target of the FKBP12-rapamycin complex, and to translate recent advances into the design of novel immunosuppressants.