Immunology Select

When cytotoxic T lymphocytes encounter an infected cell or a tumor cell, they establish an interaction interface with the target cell called the immunological synapse (IS). This interface is partly mediated by the T cell receptor (TCR). The structure of the IS resembles a ‘‘bulls-eye’’ with the TCR located in the central portion of this interface called the central supramolecular activation cluster (c-SMAC). Surrounding this region is the peripheral (p)-SMAC where adhesion molecules such as ICAM-1 cluster. Signaling initiated at the IS ultimately results in the secretion of lysosomal enzymes and lytic proteins that kill target cells. In their new study, Stinchcombe et al. (2006) describe a mechanism for how the lytic granules containing lysosomal enzymes are delivered to the plasma membrane. After establishing contact with the target cell, the microtubule organizing center (MTOC) of the T cell moves to become adjacent to the plasma membrane of the IS and the granules move along microtubules to their minus ends, which are embedded in the MTOC. To address how the granules are secreted, Stinchcombe et al. (2006) examined the cytoskeletal elements at the IS. They observed that actin was cleared away from the IS before fusion of the granules, indicating that this cytoskeletal element is not likely to participate directly in granule secretion. When they looked at the microtubule cytoskeleton they found that minus-end (but not plus-end) directed motor activity was sufficient to cause granule secretion. Once the T cell was engaged with the target cell, the authors noted that the centrosomes and centrioles were often in contact with the plasma membrane, thereby bringing microtubules parallel to the membrane. Interestingly, the centrioles were always in contact with the plasma membrane on the edge of the c-SMAC region. The authors propose that once the T cell establishes contact with a target cell, granules are transported towards the MTOC (which is in close proximity to the plasma membrane) by minus-end directed motors moving along microtubule tracks. When these granules reach the MTOC, they are delivered directly to the plasma membrane where they can fuse and release their contents. This is a very unusual secretory mechanism and it will be interesting to determine whether this system is present in other cell types. In a related study, Combs et al. (2006) propose a mechanism for how the MTOC becomes reoriented and moves closer to the IS. They examined whether the minus-end directed microtubule motor dynein is involved in MTOC reorientation. This motor is a good candidate to be involved in this event as localization of dynein to the plasma membrane and its ability to move towards the minus-end of microtubules could be a mechanism by which the centrosome is ‘reeled in’ towards the plasma membrane. The authors examined the distribution of ADAP, a scaffolding protein that links T cell signaling to clustering of integrin molecules. When Jurkat T cells were activated, ADAP, microtubules, and dynein colocalized at the IS in a ring shaped structure. ADAP also exists in a complex with dynein and this association is more pronounced in activated Jurkat cells. Loss of ADAP prevents the polarization and movement of the MTOC into the IS and dynein is not localized to the IS in ADAP-deficient T cells. These results suggest that localization of dynein to the IS mediated by ADAP could be responsible for the reorientation and movement of the MTOC to the IS. J.C. Stinchcombe et al. (2006). Nature 443, 462-465. J. Combs et al. (2006). Proc. Natl. Acad. Sci. U.S.A. 103, 14883–14888. Published online September 21, 2006. 10.1073/pnas0600914103.