Identifying the molecular control of T-cell death; on the hunt for killer genes

Apoptosis, the series of morphological changes which result from a cell-suicide program, has fascinated biologists in recent years. Identifying apoptosis regulatory and effector genes to elucidate the molecular mechanisms of programmed cell death has been a challenging but successful endeavor. However, our knowledge of this process is far from complete. The discovery of 'death genes' has provided insight into the homeostatic mechanisms regulating the immune system including the clonal deletion of self-reactive and activated lymphocytes. Notably, apoptosis induced by T-cell receptor (TCR) stimulation is the critical event which drives negative selection of thymocytes and peripheral T cells. Differential display, differential screening and subtractive hybridization have provided the technical backbone for the isolation of genes whose expression is specific for apoptotic cells. However, the genes identified by these techniques only correlate with the apoptotic phenotype and their expression may be the result of non-apoptotic pathways also affected by the death-inducing agent. Here, we review what is known about the molecular mechanisms of TCR-triggered apoptosis and discuss techniques used to isolate and characterize death regulatory molecules. In addition, we present a novel approach utilizing somatic cell genetics to clone genes involved in TCR-triggered apoptosis.