CD4+T-cells create a stable mechanical environment for force-sensitive TCR:pMHC interactions
Mechanical forces acting on ligand-engaged T-cell receptors (TCR) have previously been implicated in T-cell antigen recognition and ligand discrimination, yet their magnitude, frequency, and impact remain unclear. Here, we quantitatively assess forces across various TCR:pMHC pairs with different bond lifetimes at single-molecule resolution, both before and during T-cell activation, on platforms that either include or exclude tangential force registration. For this purpose, we use glass-supported lipid bilayers presenting pMHC conjugated to a molecular force sensor unit at its base, adhesion factors and costimulatory molecules to the approaching T-cells. Our results imply that CD4 + T-cell TCRs experience significantly lower forces than previously estimated, with only a small fraction of ligand-engaged TCRs being subjected to these forces during antigen scanning. These rare and minute mechanical forces do not impact the global lifetime distribution of the TCR:ligand bond. We propose that the immunological synapse is created as biophysically stable environment to prevent pulling forces from disturbing antigen recognition.
Authors
- René Platzer (ORCID: https://orcid.org/0009-0001-3399-4721)
- José L. Toca‐Herrera (ORCID: https://orcid.org/0000-0001-8951-2616)
- Johannes B. Huppa (ORCID: https://orcid.org/0000-0003-2634-8198)
- Lukas Schrangl (ORCID: https://orcid.org/0000-0002-0420-7872)
- Vanessa Mühlgrabner (ORCID: https://orcid.org/0009-0004-3331-8741)
- Florian Kellner (ORCID: https://orcid.org/0000-0001-5931-3798)
- Gerhard J. Schuetz (ORCID: https://orcid.org/0000-0003-1542-1089)
- Reinhard Obst (ORCID: https://orcid.org/0000-0002-4839-207X)
- Janett Göhring (ORCID: https://orcid.org/0000-0002-6755-5305)
- Josephine Wieland
- Paul Hubinger
Institutions
- Johannes Kepler University of Linz (AT)
- TU Wien (AT)
- German Cancer Research Center (DE)
- Max Delbrück Center (DE)
- Landwirtschaftliche Fachschule Tulln (AT)
- Bernstein Center for Computational Neuroscience Munich (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- BOKU University (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1038/s41467-025-62104-2
- Citations
- 4
- Primary Topic
- Force Microscopy Techniques and Applications
- Type
- article
- Field-Weighted Citation Impact
- 4.99
Funders
- Boehringer Ingelheim Fonds
- Deutsche Forschungsgemeinschaft
- Vienna Science and Technology Fund
- Austrian Science Fund