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    Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack

    Lopez, J.A. and Susanto, O. and Jenkins, M.R. and Lukoyanova, Natalya and Sutton, V.R. and Law, R.H.P. and Johnston, A. and Bird, C.H. and Bird, P I. and Whisstock, J.C. and Trapani, J.A. and Saibil, Helen R. and Voskoboinik, I. (2013) Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 121 (14), pp. 2659-2668. ISSN 0006-4971.

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    Abstract

    Cytotoxic lymphocytes serve a key role in immune homeostasis by eliminating virus-infected and transformed target cells through the perforin-dependent delivery of proapoptotic granzymes. However, the mechanism of granzyme entry into cells remains unresolved. Using biochemical approaches combined with time-lapse microscopy of human primary cytotoxic lymphocytes engaging their respective targets, we defined the time course of perforin pore formation in the context of the physiological immune synapse. We show that, on recognition of targets, calcium influx into the lymphocyte led to perforin exocytosis and target cell permeabilization in as little as 30 seconds. Within the synaptic cleft, target cell permeabilization by perforin resulted in the rapid diffusion of extracellular milieu–derived granzymes. Repair of these pores was initiated within 20 seconds and was completed within 80 seconds, thus limiting granzyme diffusion. Remarkably, even such a short time frame was sufficient for the delivery of lethal amounts of granzymes into the target cell. Rapid initiation of apoptosis was evident from caspase-dependent target cell rounding within 2 minutes of perforin permeabilization. This study defines the final sequence of events controlling cytotoxic lymphocyte immune defense, in which perforin pores assemble on the target cell plasma membrane, ensuring efficient delivery of lethal granzymes.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 23 Apr 2015 06:59
    Last Modified: 06 Dec 2016 11:14
    URI: http://eprints.bbk.ac.uk/id/eprint/11960

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