期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016857118
关键词
DNA origami; nanobiotechnology; T cell activation; pMHC; serial engagement
资金
- Austrian Science Fund (FWF) [V538-B26, I4662-B]
- PhD program Cell Communication in Health and Disease [W1205]
- TU Wien doctoral college BioInterface
- European Fund for Regional Development (EFRE, IWB2020)
- Federal State of Upper Austria
- Vienna Science and Technology Fund (WWTF) [LS13-030]
- Boehringer Ingelheim Fonds
- German Research Foundation through the Emmy Noether Program [DFG JU 2957/1-1]
- European Research Council through an ERC Starting Grant (MolMap) [680241]
- Allen Distinguished Investigator Program through The Paul G. Allen Frontiers Group
- Danish National Research Foundation (Centre for Cellular Signal Patterns) [DNRF135]
- Human Frontier Science Program through a Young Investigator Grant [HFSP RGY0065]
- Max Planck Foundation
- Max Planck Society
- International Max Planck Research School for Molecular and Cellular Life Sciences
- German Research Foundation through the Quantitative Biosciences Munich graduate school
- Wellcome Trust [100262 Z/12/Z]
- [SFB1032]
- Austrian Science Fund (FWF) [I4662] Funding Source: Austrian Science Fund (FWF)
- European Research Council (ERC) [680241] Funding Source: European Research Council (ERC)
- Wellcome Trust [100262/Z/12/Z] Funding Source: Wellcome Trust
By engineering a biomimetic interface, the study found that pairs of antibody-bound TCR5 serve as minimal receptor entities for effective TCR triggering, while transiently engaging antigenic pMHCs can also stimulate T cells effectively as isolated entities.
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.
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