DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Hellmeier, J.; Platzer, R.; Eklund, A. S.; Schlichthaerle, T.; Karner, A.; Motsch, V.; Kurz, E.; Bamieh, V.; Brameshuber, M.; Preiner, J.; Jungmann, R.; Stockinger, H.; Schuetz, G. J.; Huppa, J. B.; Sevcsik, E.

doi:10.1101/2020.06.24.166850

bioRxiv · 10.1101/2020.06.24.166850

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Hellmeier, J.·Platzer, R.·Eklund, A. S.·Schlichthaerle, T.·Karner, A.·Motsch, V.·Kurz, E.·Bamieh, V.·Brameshuber, M.·Preiner, J.·Jungmann, R.·Stockinger, H.·Schuetz, G. J.·Huppa, J. B.·Sevcsik, E.

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Abstract

T-cells detect with their T-cell antigen receptors (TCRs) the presence of rare peptide/MHC complexes (pMHCs) on the surface of antigen presenting cells (APCs). How they convert a biochemical interaction into a signaling response is poorly understood, yet indirect evidence pointed to the spatial antigen arrangement on the APC surface as 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. We found that the minimum signaling unit required for efficient T-cell activation consisted of two ligated TCRs within a distance of 20 nanometers, if TCRs were stably engaged by monovalent antibody fragments. In contrast, antigenic pMHCs stimulated T-cells robustly as well-isolated entities. These results identify the minimal requirements for effective TCR-triggering and validate the exceptional stimulatory potency of transiently engaging pMHCs.

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Hellmeier, J., Platzer, R., Eklund, A. S., Schlichthaerle, T., Karner, A., Motsch, V., Kurz, E., Bamieh, V., Brameshuber, M., Preiner, J., Jungmann, R., Stockinger, H., Schuetz, G. J., Huppa, J. B., Sevcsik, E.. 2020-06-24. DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens. https://doi.org/10.1101/2020.06.24.166850

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