Lipid order and charge protect killer T cells from accidental death

Jesse A Rudd-Schmidt,Tahereh Noori,Hyun-Jung Cho,Adrian W Hodel,Annette Ciccone,Joseph A Trapani,Bart W Hoogenboom,Jamie A Lopez,Sandra Verschoor,Ilia Voskoboinik

doi:10.1038/s41467-019-13385-x

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.

Highlights

Killer T cells maintain immune homoeostasis by eliminating virus-infected and cancerous cells
CTLs are resistant to perforin binding and lysis
We initially explored whether killer lymphocytes are intrinsically more resistant to perforin than their targets, and found that both primary activated CTLs (CD8+ T cells from BL/6 OTI transgenic mice) and natural killer cells required 10s- to 100s-fold more recombinant perforin to achieve the same level of lysis as common target cell lines (Fig. 1a)

Summary

Introduction

Killer T cells (cytotoxic T lymphocytes, CTLs) maintain immune homoeostasis by eliminating virus-infected and cancerous cells. Using TMH1-GFP-PRF, we found that CTLs (CD8+) bound less perforin than EL4 (CD8−) target cells of the same size (Fig. 1b, Supplementary Fig. 2a).

Results

Conclusion