To precisely control the nanoscale spatial arrangement of T cell-activating cues and permit remodeling after cellular contact, Hellmeier et al. anchored anti-TCR scFv or peptide-MHC (pMHC) complexes to supported lipid bilayers on a DNA origami platform. T cell activation, assessed through calcium flux and ZAP-70 recruitment, depended on anti-TCR scFv spacing; a minimum of two scFvs, especially when located adjacent to one another (10-20nm), triggered T cell activation. In contrast, a single isolated pMHC effectively induced T cell activation, suggesting serial activation of TCR clusters by a single pMHC.
Contributed by Alex Najibi
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.
Author Info: (1) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (2) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical
Author Info: (1) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (2) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090 Vienna, Austria. (3) Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Faculty of Physics and Center for Nanoscience, Ludwig Maximilian University, 80539 Munich, Germany. (4) Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Faculty of Physics and Center for Nanoscience, Ludwig Maximilian University, 80539 Munich, Germany. (5) University of Applied Sciences Upper Austria, 4020 Linz, Austria. (6) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (7) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (8) Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom. (9) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (10) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (11) University of Applied Sciences Upper Austria, 4020 Linz, Austria. (12) Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Faculty of Physics and Center for Nanoscience, Ludwig Maximilian University, 80539 Munich, Germany. (13) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090 Vienna, Austria. (14) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria. (15) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090 Vienna, Austria. (16) Institute of Applied Physics, TU Wien, 1040 Vienna, Austria; eva.sevcsik@tuwien.ac.at.
