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.