Remote Force Modulation of the T-Cell Receptor Reveals an NFAT-Threshold for CD4⁺ T-Cell Activation

Mechano-modulation of cell surface proteins to influence cell activation has been shown as a promising new advanced therapy for regenerative medicine applications. These strategies rely on the manipulation of mechanosensitive cell surface receptors to initiate intracellular signal transduction. The cell surface receptor of T lymphocytes (TCR), which recognises peptide-MHC molecules central to driving the adaptive immune response, has recently been suggested to be mechano-responsive. Despite this advance, little is known as to whether the TCR can be mechanically modulated to achieve TCR signalling and subsequent T-cell activation, and whether these characteristics can be exploited for immunotherapies. Here, we describe a magnetic particle-based platform for mechanical modulation of the TCR and outline how this platform can be utilised to achieve CD4⁺ T-cell activation. We demonstrate that mechanical manipulation of the TCR induces cell surface clustering of the TCR and downstream TCR signalling, leading to eventual TCR downregulation and T-cell activation. We investigate the temporal relationship between mechanical modulation of the TCR and subsequent T-cell activation, thereby identifying that accumulation of signalling events within the NFAT pathway is required to reach the threshold required for CD4⁺ T-cell activation, outlining an axis which controls the CD4⁺ T-cell response to external mechanical cues. These findings identify how CD4⁺ T cells can modulate their function in response to such cues while also outlining a remote-magnetic particle-based platform that may be used for the control of T-cell responses.