TCRs alive on the periphery

TCRs alive on the periphery eeping T cell receptors (TCRs) away from the center of the immunological synapse boosts stimulatory stignals, based on work from The immunological synapse—the cell–cell junction between a T cell and antigen-presenting cell (APC)—looks like a bull's eye, with a central cluster of TCRs and their bound antigen–MHC ligands surrounded by a ring of adhesion molecules and their ligands. Active TCR clusters form at the periphery but then move toward the center, where they stop signaling. To determine whether this change of locale is necessary for TCR shutdown, the group blocked the inward transport. They first replaced the APC with a supported lipid bilayer containing antigen– MHC and an adhesion ligand. They then etched chromium barriers onto the substrate to form variously patterned corrals within which MHC-bound TCRs would be trapped. show that flies lacking neuronal p53 activity live longer. Hyperactivation of p53, which kills DNA-damaged cells, reduces tumor incidence in mammals but also shortens their life span. These earlier findings suggested that reducing p53 activity might increase life span. Helfand's group found that this did not pan out for flies lacking all p53—they died earlier than normal, probably because of the requirement for p53 in developmental apoptosis. But if the authors blocked p53 activity only in neurons, the flies lived longer healthy lives and were also more resistant to DNA-damaging agents. Loss of p53 only in the fat body or muscle tissue did not extend life span. " Maybe, " says Helfand, " the nervous system is the weak link. If it goes [via p53-mediated apoptosis, for example], the rest of the body goes. " The group does not yet know whether neurons survive longer in the p53 mutants due to less apoptosis, but they provide evidence that traditional caspase-dependent apoptosis is probably not affected. The involvement of caspase-independent apoptosis has not been ruled out. Another possibility is that the neuronal tinkering causes systemic effects, perhaps via the neuroendocrine system. Indeed, calorie restriction also increases life span in flies, and p53 inhibition N TCRs that were stuck in peripheral corrals signaled longer, as measured by their phosphorylation status and ability to elevate cytoplasmic calcium levels. " It's not just a matter of timing, " says Dustin. " Location of the TCR clusters is important. " It is not clear whether the periphery is a particularly good environment to sustain signaling, the center is a particularly …