T cell mechanomemory takes training: cell-secreted factors reinforce short-term mechanosensing into long-term proliferation

Biomaterials provide a powerful tool for directing the function of T cells with applications from fundamental immunology research to immunotherapy. Intriguingly, controlling the mechanical stiffness of biomaterials used to activate T cells modulates a range of subsequent functions from early activation to differentiation. However, it is not fully understood whether the effect of initial, short-term mechanosensing is limited to immediate impacts on cell function or imparts a long-lasting imprint on cell function. This report demonstrates such a mechanomemory in the context of expansion; T cells activated on mechanically soft surfaces exhibit an extended proliferative phase for multiple generations following removal from the substrate. This effect results from a combination of cell-intrinsic changes and extrinsic factors associated with cell-cell signaling. Specifically, activation using a soft elastomer substrate extends subsequent proliferation over multiple cell divisions. This programming can initially be modified by extrinsic soluble factors secreted into the media; the conditioned media carries information about early mechanosensitive activation, as demonstrated using media exchange experiments. Notably, the impact of extrinsic factors on proliferation decreases over the course of expansion, showing that reinforcement of mechanosensing leads to establishment of mechanomemory. Together, these results suggest that populations of T cells can be trained to retain the mechanical imprint of an activating surface through continued reinforcement, potentially directing later function in a range of immunotherapy applications.