LAUSR

Cell Biology Cytotoxic T lymphocytes (CTLs) recognize and destroy infected or malignant cells. CTLs secrete the pore-forming protein perforin into the immune synapse, where perforin disrupts the target cell plasma membrane and initiates cell death pathways. Paradoxically, the secreted perforin only damages the target cell, leaving the producer lymphocytes unscathed and able to attack another target cell. What protects the lymphocyte is unclear. Using a variety of approaches, Rudd-Schmidt et al. found that two distinct but coordinated mechanisms were deployed by CTLs to protect themselves. Both mechanisms depended on the dynamic regulation of plasma membrane lipid composition and topology. High membrane lipid order made the CTL presynaptic membrane refractory to perforin binding. Furthermore, phosphatidylserine, exposed on the killer cell membrane, appeared to bind and inactivate perforin. Nat. Commun. 10 , 5396 (2019).