Mechanical force determines chimeric antigen receptor microclustering and signaling.
Mol Ther
; 32(4): 1016-1032, 2024 Apr 03.
Article
en En
| MEDLINE
| ID: mdl-38327049
ABSTRACT
Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from â¼12 to â¼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.
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Banco de datos:
MEDLINE
Asunto principal:
Receptores Quiméricos de Antígenos
Idioma:
En
Año:
2024
Tipo del documento:
Article