Research highlights
T cell activation: Fine-tuning the immunological synapse
Nature Reviews Immunology 9, 5 (01 May 2009) | doi:10.1038/nri2557
Standfirst
Activation of T cells by antigen-presenting cells (APCs) requires the formation of a specific and long-lasting interface between the two cells, known as the immunological synapse. A recent study by Michael Dustin and colleagues shows that the actin-based motor protein myosin IIA has a central role in the formation and persistence of the immunological synapse and in signalling downstream of the T cell receptor (TCR).
STOCKBYTETCR engagement results in the immediate actin-dependent formation of TCR microclusters and recruitment of signalling components to the outer parts of the T cell–APC contact area. The TCR microclusters then move to the centre of the contact area and combine to form the central supramolecular activation cluster (cSMAC) of the immunological synapse. This inwards (centripetal) movement of the microclusters sustains TCR signalling and depends on filamentous actin. But how the microclusters are coupled to actin to result in this centripetal movement is not known.
...the actin-based motor protein myosin IIA has a central role in the formation and persistence of the immunological synapse...
As actin-based myosin IIA has previously been shown to be recruited to the immunological synapse, the authors examined its role in TCR signalling and microcluster formation. They showed that engagement of the TCR resulted in the rapid phosphorylation of myosin IIA (within 30 seconds) and its recruitment to TCR microclusters. Inhibition of myosin II ATPase activity by the inhibitor blebbistatin or depletion of myosin IIA using small interfering RNA reduced microcluster centripetal movement.
Blebbistatin treatment before stimulation through the TCR did not block the formation of small microclusters, but these microclusters did not form larger clusters. In addition, phosphorylation of the signalling components ZAP70 (
-chain-associated protein kinase of 70 kDa) and LAT (linker for activation of T cells), but not the upstream kinase LCK, was reduced. Treatment with blebbistatin after conjugate formation resulted in immunological synapse instability and a rapid decrease in cytoplasmic Ca2+ concentration (one of the earliest signalling events that occurs following TCR engagement). The decrease in Ca2+ concentration preceded immunological synapse instability and was independent of the amount of stimulus.
So, myosin IIA is required for the accumulation of microclusters and their centripetal movement, for the formation and stabilization of the immunological synapse and for the amplification of TCR signalling between LCK and ZAP70.
ORIGINAL RESEARCH PAPER
- Ilani, T. et al. T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Nature Immunol. 6 Ap 2009 (doi:10.1038/ni.1723) | Article |
