Multivalent Presentation of TCRs on DNA Nanostructures as a Sensitive Probe for pMHC Detection

Dendritic cells (DCs) are key regulators of immune responses, presenting antigen-derived peptides on major histocompatibility complexes (pMHCs) to T cells for recognition via their T cell receptors (TCRs). Despite the weak intrinsic affinity of the TCR-pMHC interaction, T cells exhibit remarkable specificity and sensitivity in detecting and responding to antigenic peptides even at very low concentrations. However, directly probing pMHC complexes on cell surfaces remains technically challenging, particularly when they are presented at low levels due to the limited sensitivity and/or specificity of existing probes. Here, we leveraged the structural nanoscale precision of DNA origami to transform the high specificity, but low intrinsic affinity, of TCRs into high affinity probes with programmable binding profiles. We demonstrate that our approach has the potential to perform better than conventional TCR-like antibodies in sensitivity, providing a promising strategy for facilitating the study of antigen presentation.