CD4+T-cells create a stable mechanical environment for force-sensitive TCR:pMHC interactions

Lukas Schrangl, Florian Kellner, René Platzer, Vanessa Mühlgrabner, Paul Hubinger, Josephine Wieland, Reinhard Obst, José L. Toca-Herrera, Johannes B. Huppa, Gerhard J. Schütz and Janett Göhring ()
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Lukas Schrangl: University of Natural Resources and Life Sciences
Florian Kellner: Medical University of Vienna
René Platzer: Medical University of Vienna
Vanessa Mühlgrabner: Medical University of Vienna
Paul Hubinger: Medical University of Vienna
Josephine Wieland: Ludwig-Maximilians-Universität München
Reinhard Obst: Ludwig-Maximilians-Universität München
José L. Toca-Herrera: University of Natural Resources and Life Sciences
Johannes B. Huppa: Medical University of Vienna
Gerhard J. Schütz: TU Wien
Janett Göhring: Medical University of Vienna

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62104-2

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