Lipid order and charge protect killer T cells from accidental death

Jesse A. Rudd-Schmidt, Adrian W. Hodel, Tahereh Noori, Jamie A. Lopez, Hyun-Jung Cho, Sandra Verschoor, Annette Ciccone, Joseph A. Trapani, Bart W. Hoogenboom () and Ilia Voskoboinik ()
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Jesse A. Rudd-Schmidt: Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre
Adrian W. Hodel: University College London
Tahereh Noori: Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre
Jamie A. Lopez: Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre
Hyun-Jung Cho: The University of Melbourne
Sandra Verschoor: Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre
Annette Ciccone: Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre
Joseph A. Trapani: University of Melbourne
Bart W. Hoogenboom: University College London
Ilia Voskoboinik: Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Killer T cells (cytotoxic T lymphocytes, CTLs) maintain immune homoeostasis by eliminating virus-infected and cancerous cells. CTLs achieve this by forming an immunological synapse with their targets and secreting a pore-forming protein (perforin) and pro-apoptotic serine proteases (granzymes) into the synaptic cleft. Although the CTL and the target cell are both exposed to perforin within the synapse, only the target cell membrane is disrupted, while the CTL is invariably spared. How CTLs escape unscathed remains a mystery. Here, we report that CTLs achieve this via two protective properties of their plasma membrane within the synapse: high lipid order repels perforin and, in addition, exposed phosphatidylserine 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. Furthermore, these mechanisms imply an unsuspected role for plasma membrane organization in protecting cells from immune attack.

Date: 2019
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DOI: 10.1038/s41467-019-13385-x

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