Centrosomes (red) go right to the membrane (green) to deliver toxic granules at the synapse

GRIFFITHS/MACMILLAN

Just as a deadly martial arts master channels his inner chi to deliver a fatal strike, cytotoxic T cells (CTLs) channel their toxic secretory granules to strike an infected target cell. New work by Jane Stinchcombe, Gillian Griffiths, and colleagues (Sir William Dunn School of Pathology, Oxford, UK) reveals that centrosomes do this channeling, going right to the plasma membrane to deliver their secretory granule death blows.

A CTL targets an infected cell by making transitory contact via an immunological synapse. Lytic protein–containing secretory granules are then released at the synapse to kill the target. Trafficking of the granules to the synapse was known to require transport along microtubules, but just how granules were delivered was unknown.

The general assumption was that CTLs would deliver their secretory granules in the same way that melanocytes deliver pigment for secretion—by transporting it along microtubules, transferring it to the actin cytoskeleton, and then delivering it to the membrane. Griffiths's group thus looked at actin in CTLs, but found that it is completely cleared away from the synapse.

The authors found that secretory granule movement toward the minus ends of microtubules was sufficient for killing target cells. Granules thus move toward the centrosome, which associates with microtubule minus ends, not toward plus ends at the plasma membrane.

The team observed that the centrosome itself associates with the membrane in a large number of synapses. They hypothesize that the action of clearing the actin might, via actins' attachment to microtubules, pull the centrosome close enough to the synapse membrane to send out the granules directly. Griffiths proposes that such direct delivery, without the need for transfer to the actin cytoskeleton, might also explain how the same CTL can engage and disengage synapses rapidly to kill multiple target cells, much like Bruce Lee rapidly defeats multiple opponents when surrounded.

Reference:

Stinchcombe, J.C., et al.
2006
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Nat. Cell Biol.
doi:.