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Published on: February 28, 2019
Mechanical force determines chimeric antigen receptor microclustering and signaling
Yue Qiu1, Qingyue Xiao1, Yucai Wang1
1Institute of Molecular Immunology, Department of Biotechnology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
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 ∼12 to ∼51 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.
Insights
Chimeric antigen receptor (CAR) T-cell activation relies on mechanical force. This study reveals that antigen engagement triggers CAR microclustering and signaling through mechanical forces generated by cell contractility.
Area of Science:
- Immunology
- Cellular Biology
- Biophysics
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is a successful clinical treatment.
- The precise mechanism initiating CAR signaling upon antigen binding is not fully understood.
Purpose of the Study:
- To investigate the role of mechanical force in CAR T-cell activation.
- To decouple microclustering and signaling events in CAR T-cells.
Main Methods:
- Utilized double-stranded DNA (dsDNA) tethers to apply controlled mechanical forces (12–51 pN) to antigens.
- Manipulated antigen tether forces to isolate microclustering and signaling.
Main Results:
- CAR microclustering and signaling are dependent on mechanical force during antigen binding.
- Cellular contractility generates the mechanical force for CAR microclustering.
- Strong adhesion and CAR diffusion confinement, driven by mechanical force, induce microclustering.
- Cytotoxicity may require a lower mechanical force threshold than cytokine generation.
Conclusions:
- CAR signaling is initiated by mechanical-force-induced microclustering.
- This study proposes a model where mechanical forces mediate CAR T-cell activation.
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