Remote force modulation of the T-cell receptor reveals an NFAT-threshold for CD4 ⁺ T cell activation

Mechano-modulaCon of cell surface proteins to influence cell acCvaCon has been shown as a promising new advanced therapy for regeneraCve medicine applicaCons. These strategies rely on the manipulaCon of mechanosensiCve cell surface receptors to iniCate intracellular signal transducCon. The cell surface receptor of T lymphocytes (TCR), which recognises pepCde-MHC molecules central to driving the adapCve immune response, has recently been suggested to be mechano-responsive. Despite this advance, li]le is known as to whether the TCR can be mechanically modulated to achieve TCR signalling and subsequent T cell acCvaCon, and whether these characterisCcs can be exploited for immunotherapies. Here, we describe a magneCc parCcle-based pla_orm for mechanical modulaCon of the TCR and outline how this pla_orm can be uClised to achieve CD4 ⁺ T cell acCvaCon. We demonstrate that mechanical manipulaCon of the TCR induces cell surface clustering of the TCR and downstream TCR signalling, leading to eventual TCR downregulaCon and T cell acCvaCon.

We invesCgate the temporal relaConship between mechanical modulaCon of the TCR and subsequent T cell acCvaCon, hereby idenCfying that accumulaCon of signalling events within the NFAT-pathway is required to reach the threshold required for CD4 ⁺ T cell acCvaCon, outlining an axis which controls the CD4 ⁺ T cell response to external mechanical cues. These findings idenCfy how CD4 ⁺ T cells can modulate their funcCon in response to such cues, whilst also outlining a remote-magneCc parCcle-based pla_orm that may be used for the control of T cell responses.