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Zhou, Yabo; Wang, Dianheng; Zhou, Li; Zhou, Nannan; Wang, Zhenfeng; Chen, Jie; Pang, Ruiyang; Fu, Haixia; Huang, Qiusha; Dong, Fang; Cheng, Hui; Zhang, Huafeng; Tang, Ke; Ma, Jingwei; Lv, Jiadi; Cheng, Tao; Fiskesund, Roland; Zhang, Xiaohui; Huang, Bo

Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing

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  • Media type: E-Article
  • Title: Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
  • Contributor: Zhou, Yabo; Wang, Dianheng; Zhou, Li; Zhou, Nannan; Wang, Zhenfeng; Chen, Jie; Pang, Ruiyang; Fu, Haixia; Huang, Qiusha; Dong, Fang; Cheng, Hui; Zhang, Huafeng; Tang, Ke; Ma, Jingwei; Lv, Jiadi; Cheng, Tao; Fiskesund, Roland; Zhang, Xiaohui; Huang, Bo
  • imprint: Springer Science and Business Media LLC, 2024
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-024-45750-w
  • ISSN: 2041-1723
  • Keywords: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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.</jats:p>
  • Access State: Open Access