What Keeps a Resting T Cell Alive?

The controls of quiescent lymphocyte survival remainpoorly understood. Recently, adoptive transfer experiments have suggested that ongoing signal transductionthrough the T-cell receptor is required to keep both naiveand memory T cells alive. This signaling results in thepromotion of cellular survival in the absence of proliferation. One common feature of the signal transductionpathways that promote survival is the ability to stimulatecellular metabolism. It appears that there is a minimal rateof cellular metabolism to maintain intracellular homeostasis of organelles such as mitochondria and the endoplasmic reticulum. In the absence of external stimulation,cells are unable to maintain a sufficient metabolic rate tomaintain organelle homeostasis. The loss of survival factor-induced glycolysis results in progressive changes inmitochondria that culminate in cytochrome c release. Release of cytochrome c induces the activation of caspasesand results in apoptosis. The Bcl-2-related protein, BclxL, allows cells to survive at lower rates of cellularmetabolism by promoting mitochondrial adaptationthrough the ability to facilitate adenine nucleotide exchange between the mitochondrial matrix and the cytosol.These data suggest that one mechanism by which Bcl-2-related proteins maintain cell survival is by promotingadaptation of mitochondria to changing bioenergetic requirements of the cell. The ability of Bcl-2 proteins topromote cell survival in the absence of extrinsic survivalsignals may explain why Bcl-2 is critical for the survivalof naive T cells and may account for why overexpressionof either Bcl-2 or Bcl-xL leads to an expansion in thenumber of both naive and memory cells...