T cell cytoskeletal forces shape synapse topography for targeted lysis via membrane curvature bias of perforin.
Dev Cell
; 57(18): 2237-2247.e8, 2022 09 26.
Article
en En
| MEDLINE
| ID: mdl-36113483
ABSTRACT
Cytotoxic T lymphocytes (CTLs) lyse target cells by delivering lytic granules that contain the pore former perforin to the cytotoxic immunological synapse. Here, we establish that opposing cytoskeletal forces drive lytic granule polarization and simultaneously shape T cell synapse topography to enhance target perforation. At the cell rear, actomyosin contractility drives the anterograde movement of lytic granules toward the nucleus. At the synapse, dynein-derived forces induce negatively curved membrane pockets to which granules are transported around the nucleus. These highly concave degranulation pockets are located directly opposite positively curved bulges on the target cell membrane. We identify a curvature bias in the action of perforin, which preferentially perforates positively curved tumor cell membrane. Together, these findings demonstrate murine and human T cell-mediated cytotoxicity to be a highly tuned mechano-biochemical system, in which the forces that polarize lytic granules locally bend the synaptic membrane to favor the unidirectional perforation of the target cell.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Actomiosina
/
Citotoxicidad Inmunológica
/
Perforina
/
Sinapsis Inmunológicas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia