Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 Feb 2024
15 Feb 2024
Historique:
received:
12
03
2023
accepted:
03
02
2024
medline:
16
2
2024
pubmed:
16
2
2024
entrez:
15
2
2024
Statut:
epublish
Résumé
Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.
Identifiants
pubmed: 38360940
doi: 10.1038/s41467-024-45750-w
pii: 10.1038/s41467-024-45750-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1405Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81788101
Informations de copyright
© 2024. The Author(s).
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