Precise regulating T cell activation signaling with spatial controllable positioning of receptors on DNA origami

Adoptive immunotherapy requires controllable T cell proliferation to achieve a desirable immune response. The nanoscale spatial distribution of T cell receptor (TCR) within the interface between T cell and antigen-presenting cell (APC) (also known as immunological synapse) is an essential factor to initiate immune signals. However, it remains challenging to establish a correlation between the spatial distribution of TCR, including valent, spacing, and geometric arrangement, with triggered immune response. In the present study, we introduce DNA origami with precisely positioned TCR ligands loading as a mimic of the immunological synapse to evaluate the spatial effect of TCR on T cell signaling. Through monitoring early and late signals of T cell activation, we demonstrate a tuneable T cell activation response. Our findings suggest that early and late T cell signals have different responses to the spatial distribution of TCR. The proposed DNA origami platform holds great potential for precisely regulating T cell activation in adoptive immunotherapy.