Stages of T cell activation: multiple targets for immunosuppressive agents. Signal 1: stimulation of T cell receptor (TCR) results in calcineurin activation, a process inhibited by cyclosporin (CyA) and tacrolimus. Calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), enabling it to enter the nucleus and bind to interleukin-2 gene promoter. Corticosteroids inhibit cytokine gene transcription in lymphocytes and antigen-presenting cells by several mechanisms. Signal 2: co-stimulatory signals are necessary to optimize T cell interleukin-2 gene transcription, prevent T cell anergy, and inhibit T cell apoptosis. Experimental agents, but not current immunosuppressive agents, interrupt these intracellular signals. Signal 3: stimulation of interleukin-2 receptor induces the cell to enter the cell cycle and proliferate. Signal 3 can be blocked by interleukin-2 receptor antibodies or by sirolimus, which inhibits second messenger signals induced by the ligation of interleukin-2 receptor. After progression into the cell cycle, azathioprine and mycophenolate mofetil (MMF) interrupt DNA replication by inhibiting purine synthesis. Reproduced with permission from ..