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Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.
- Source :
- Nature Communications; 2/19/2024, Vol. 15, p1-16, 16p
- Publication Year :
- 2024
-
Abstract
- 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. Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia. [ABSTRACT FROM AUTHOR]
- Subjects :
- CYTOTOXIC T cells
T cells
CANCER cells
YAP signaling proteins
PERFORINS
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 15
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 175798712
- Full Text :
- https://doi.org/10.1038/s41467-024-45750-w