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.

Details

Title
Lipid order and charge protect killer T cells from accidental death
Author
Rudd-Schmidt, Jesse A 1 ; Hodel, Adrian W 2 ; Noori, Tahereh 3 ; Lopez, Jamie A 4 ; Hyun-Jung, Cho 5 ; Verschoor, Sandra 6 ; Ciccone, Annette 6 ; Trapani, Joseph A 7 ; Hoogenboom, Bart W 8   VIAFID ORCID Logo  ; Voskoboinik, Ilia 1 

1  Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia 
2  London Centre for Nanotechnology, University College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK 
3  Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
4  Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Bristol-Myers Squibb, 4 Nexus Ct, Mulgrave, VIC, Australia 
5  Biological Optical Microscopy Platform, The University of Melbourne, Parkville, VIC, Australia 
6  Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
7  Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
8  London Centre for Nanotechnology, University College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK; Department of Physics and Astronomy, University College London, London, UK 
Pages
1-13
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13385-x
ProQuest document ID
2319186174
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.