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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,J. Toca-Herrera,Johannes B. Huppa,Gerhard J. Schütz,Janett Göhring

Published 2024 in bioRxiv

ABSTRACT

Mechanical forces acting on ligand-engaged T-cell receptors (TCRs) have previously been implicated in T-cell antigen recognition and ligand discrimination, yet their magnitude, frequency, and impact remain unclear. 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. 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.

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