The Strength of T Cell Receptor Signal Controls the Polarization of Cytotoxic Machinery to the Immunological Synapse

Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
Immunity (Impact Factor: 21.56). 10/2009; 31(4):621-31. DOI: 10.1016/j.immuni.2009.08.024
Source: PubMed


Killing by cytotoxic T lymphocytes (CTLs) is mediated by the secretion of lytic granules. The centrosome plays a key role in granule delivery, polarizing to the central supramolecular activation complex (cSMAC) within the immunological synapse upon T cell receptor (TCR) activation. Although stronger TCR signals lead to increased target cell death than do weaker signals, it is not known how the strength of TCR signal controls polarization of the centrosome and lytic granules. By using TCR transgenic OT-I CTLs, we showed that both high- and low-avidity interactions led to centrosome polarization to the cSMAC. However, only high-avidity interactions, which induced a higher threshold of intracellular signaling, gave rise to granule recruitment to the polarized centrosome at the synapse. By controlling centrosome and granule polarization independently, the centrosome is able to respond rapidly to weak signals so that CTLs are poised and ready for the trigger for granule delivery.

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Available from: Misty Jenkins
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    • "Previous studies have shown that phosphorylated ERK may play a role in actin reorganisation as ERK co-localises with actin at the immune synapse, is implicated in granule and MTOC polarisation, and is required for CTL degranulation (Robertson et al., 2005; Jenkins et al., 2009). "
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    ABSTRACT: T cell receptor (TCR) activation leads to a dramatic reorganisation of both membranes and receptors as the immunological synapse forms. Using a genetic model to rapidly inhibit Zap70 catalytic activity we examined synapse formation between cytotoxic T lymphocytes and their targets. In the absence of Zap70 catalytic activity Vav-1 activation occurs and synapse formation is arrested at a stage with actin and integrin rich interdigitations forming the interface between the two cells. The membranes at the synapse are unable to flatten to provide extended contact, and Lck does not cluster to form the central supramolecular activation cluster (cSMAC). Centrosome polarisation is initiated but aborts before reaching the synapse and the granules do not polarise. Our findings reveal distinct roles for Zap70 as a structural protein regulating integrin-mediated control of actin vs its catalytic activity that regulates TCR-mediated control of actin and membrane remodelling during formation of the immunological synapse. DOI:
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    • "Although formation of a stable immune synapse between CTL and target cell may not be required for CTL cytolytic activity [55], high avidity CTL/target cell interactions such as those involving the CD8+ OT1 CTL/OVA peptide-loaded target cell system used in our study have been shown to lead to granule polarization to the immune synapse [56]. Accordingly, in our live video experiments, we observed the movement of the red GZMB-Tom granules towards the CTL/target cell tight interaction zone corresponding to the immune synapse. "
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    • "Shortly after, this molecular pattern is inverted forming a central cluster of TCR/pMHC molecules known as central supramolecular activation cluster (cSMAC), which is surrounded by a peripheral ring of LFA- 1/ICAM-1 molecules and is named the peripheral supramolecular activation cluster (pSMAC) [20, 78–80], defining a mature IS. Importantly, this process depends on significant cytoskeleton rearrangements involving the microtubule organizing center (MTOC) and cytotoxic granules polarizing to the IS [81] [82] [83]. In fact, disruption of actin polymerization by cytochalasin D has been shown to disrupt IS formation [84] [85]. "
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