Proc. Natl Acad. Sci. https://doi.org/10.1073/pnas.1904034116 (2019)

Forces transmitted via interactions between the T cell antigen receptor (TCR) and its peptide–major histocompatibility complex ligand are generally weak and fleeting, which makes study of these interactions challenging. In the Proceedings of the National Academy of Sciences, Salaita and colleagues use a fluorescent DNA hairpin probe coupled to TCR ligands (antibody to the TCR invariant chain CD3ε or peptide–major histocompatibility complex) that unfolds when force over a definable threshold is applied. Normally the hairpin refolds rapidly, but this modified probe can be selectively and reversibly ‘locked’ open, which allows measurement of the highly transient forces generated by TCR–ligand interactions. Force maps show that cognate peptides generate a characteristic ring structure, whereas altered peptide ligands or interactions between the inhibitory receptor PD-1 and its ligand PD-L1 are highly disorganized. This modified DNA-probe approach for measuring transient forces may be widely applicable across immunological systems.