1. DNA origami demonstrate the unique stimulatory power of single pMHCs as T cell antigens
- Author
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Johannes B. Huppa, Ralf Jungmann, Gerhard J. Schütz, Andreas Karner, Viktoria Motsch, Elke Kurz, Joschka Hellmeier, Hannes Stockinger, Eva Sevcsik, Magdalena C. Schneider, Alexandra S. Eklund, Johannes Preiner, Victor Bamieh, René Platzer, Thomas Schlichthaerle, and Mario Brameshuber
- Subjects
CD4-Positive T-Lymphocytes ,Cell signaling ,T cell ,Lipid Bilayers ,Primary Cell Culture ,Receptors, Antigen, T-Cell ,Antigen-Presenting Cells ,Gene Expression ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,Ligands ,Lymphocyte Activation ,Major Histocompatibility Complex ,Mice ,Antigen ,medicine ,DNA origami ,Animals ,Multidisciplinary ,biology ,Chemistry ,T-cell receptor ,DNA ,Biological Sciences ,Ligand (biochemistry) ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Phosphatidylcholines ,Nucleic Acid Conformation ,Receptor clustering ,Spleen ,Protein Binding ,Signal Transduction ,Single-Chain Antibodies - 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 (APCs). 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 TCRs via stably binding monovalent antibody fragments, we found the minimum signaling unit promoting efficient T cell activation to consist of two antibody-ligated TCRs 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 TCRs as minimal receptor entities for effective TCR triggering yet validate the exceptional stimulatory potency of single isolated pMHC molecules.
- Published
- 2021