Oral Presentation Lorne Infection and Immunity 2020

The killer's armour: Lipid order and charge protect killer T cells from accidental death (#40)

Jesse Rudd-Schmidt 1 , Adrian Hodel 1 2 , Joseph Trapani 1 , Bart Hoogenboom 2 , Ilia Voskoboinik 1
  1. Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. University College London, London, United Kingdom

Killer T cells (cytotoxic T lymphocytes, CTLs) are responsible for maintaining immune homoeostasis by eliminating virus-infected and cancerous cells (1).

CTLs bind to, and form an immunological synapse with their targets, then secrete a Ca2+-dependent pore-forming protein (perforin) and a cocktail of pro-apoptotic serine proteases (granzymes) into the synaptic cleft.

Although the CTL and the target cell plasma membranes are both exposed to perforin within the synapse, only the target cell membrane is disrupted by perforin pores. As a consequence, granzymes will penetrate and kill the target cell, while the CTL is invariably spared (2). What governs CTL resistance to its own secreted perforin is one of the most enigmatic questions in the field.

By using a combination of immunological, biochemical and biophysical techniques, including the atomic force microscopy (3), we discovered that CTLs remain protected from their own secreted perforin via the physical properties of their plasma membrane within the synapse. Thus, we identified two protective mechanisms: the CTL membrane repels perforin due to its high lipid order and, in addition, it exposes phosphatidylserine within the synapse, which by its negative charge sequesters and inactivates perforin

The resulting resistance of CTLs to perforin explains their ability to kill target cells in rapid succession and to survive these encounters, thus enabling CTLs to maintain immune homoeostasis.

  1. Voskoboinik, I., Whisstock, J.C. and Trapani, J.A. (2015) Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 15:388-400.
  2. Lopez, J.A., Susanto, O., Jenkins, M.R., Lukoyanova, N., Sutton, V.R., Law, R.H.P., Johnston, A., Bird, C.H., Bird, P.I., Whisstock, J.C., Trapani, J.A., Saibil, H.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: 2659-2668.
  3. Leung, C., Hodel, A.W., Brennan, A.J., Lukoyanova, N., Tran, S., House, C.M., Kondos, S.C., Whisstock, J.C., Dunstone, M.A., Trapani, J.A., Voskoboinik, I.*, Saibil, H.R.*, and Hoogenboom, B.W.* (2017) Real-time visualization of perforin nanopore assembly. Nature Nanotech, 12:467-473. (* joint senior authors)