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Free keywords:
SUPERRESOLUTION MICROSCOPY; RECEPTOR MICROCLUSTERS; LIGAND RECOGNITION;
PLASMA-MEMBRANE; ACTIVATION; BINDING; KINETICS; THRESHOLDSScience & Technology - Other Topics; DNA origami; nanobiotechnology; T cell activation; pMHC; serial
engagement;
Abstract:
T cells detect with their T cell antigen receptors (TCRs) the presence of rare agonist peptide/MHC complexes (pMHCs) on the surface of antigen-presenting cells (APC5). How extracellular ligand binding triggers intracellular signaling is poorly understood, yet spatial antigen arrangement on the APC surface has been suggested to be a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering. When targeting TCR5 via stably binding monovalent antibody fragments, we found the minimum signaling unit promoting efficient T cell activation to consist of two antibody-ligated TCR5 within a distance of 20 nm. In contrast, transiently engaging antigenic pMHCs stimulated T cells robustly as well-isolated entities. These results identify pairs of antibody-bound TCR5 as minimal receptor entities for effective TCR triggering yet validate the exceptional stimulatory potency of single isolated pMHC molecules.
