Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack
Jamie A Lopez, Olivia Susanto, Misty R Jenkins, Natalya Lukoyanova, Vivien R Sutton, Ruby HP Law, Angus Johnston, Catherina H Bird, Phillip I Bird, James C Whisstock, Joseph A Trapani, Helen R Saibil, Ilia Voskoboinik
BLOOD | AMER SOC HEMATOLOGY | Published : 2013
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, targe..View full abstract
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Awarded by Biotechnology and Biological Sciences Research Council
J.A.L. is supported by a National Health and Medical Research Council (NHMRC) postdoctoral training fellowship. O.S. is supported by a Cancer Research Institute predoctoral tumor immunology scholarship. M.R.J. is supported by an NHMRC/R.G. Menzies postdoctoral training fellowship. I. V., J.A.T., P. I. B., and J.C.W. are supported by fellowships and grants from the NHMRC. J.C.W. is an Australian Research Council Federation Fellow. H. R. S. thanks the Wellcome Trust and the UK Biotechnology and Biological Sciences Research Council for support.