Pim-1 and Pim-2 are essential for T cell growth and survival in the presence of rapamycin.

T cell survival in the face of the immunosuppressive drug rapamycin depends on the expression of prosurvival proteins Pim-1 and Pim-2, according to a report by Fox et al. on page 259. Pim-1 and Pim-2 transmit signals that compensate for those that are wiped out by rapamycin; without the Pim proteins, rapamycin is deadly.

Rapamycin, a drug used to prevent rejection of transplants in humans, blocks the activation of a protein kinase called TOR (target of rapamycin), a component of a T cell signaling pathway that is important for cell survival and activation. Rapamycin works in transplant patients, but treatment of T cells with this drug in vitro or elimination of a signaling protein upstream of TOR in mice has little effect on T cell activation or survival. This paradox, says senior author Craig Thompson, is “rapamycin's dirty little secret.” The new work establishes the mechanism behind half of this secret.Thompson's group now shows that rapamycin's lack of effect in vitro and in mice is due to the expression of protein kinases Pim-1 and Pim-2, which are activated by growth-promoting cytokines and TCR ligation. T cells lacking both Pim proteins and treated with rapamycin failed in two respects: they did not turn on activation signals in response to TCR ligation and they were unable to respond to cytokine-driven survival signals. Wild-type cells, however, activated the TCR pathway and survived as well as untreated cells. Thus, the Pim proteins provide the only alternative signaling pathway that can bypass the defect inflicted by rapamycin.

The debilitating consequences of lacking Pim-1 and Pim-2 are in part due to an inability to phosphorylate and thus inactivate the proapoptotic protein Bad. Without the Pim proteins, Bad runs rampant. Whether activated Bad is the sole cause of the effects seen in the absence of Pim-1 and Pim-2 is not yet known, but future studies using Bad-deficient mice will reveal if other mechanisms are also at play. Why rapamycin works in patients who have no known defects in the Pim proteins remains a mystery.