Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds

T cells recognize antigens through T cell receptor (TCR) interactions with peptide-major histocompatibility complex (pMHC) assisted by the CD4 or CD8 coreceptors depending on the MHC class. Under force, TCR-pMHC interactions form catch or slip bonds whose profiles have been proposed to shape TCR triggering and ligand discrimination, but their predictive value, particularly in the presence of coreceptor engagement, remains incompletely characterized.

Built upon our recent correlative analysis of TCR-pMHC bimolecular catch bonds with T cell function, we analyzed 27 paired TCR-pMHC datasets measured under conditions that either prevented or permitted CD8 or CD4 co-engagement, drawn from multiple laboratories, cell types and measurement techniques, supplemented with a set of new experiments, to correlate 2D and 3D biophysical parameters with antigen-induced T cell responses.

We found that metrics extracted from force-dependent bond lifetime curves (e.g. the optimal force and catch bond intensity) predict T cell activation and thymocyte selection better than force-free parameters measured either in situ at the T cell membrane or in fluid phase using purified ectodomain proteins, both when coreceptor contributions are absent and present. Moreover, CD8 co-engagement with pMHC systematically increases these metrics and improves TCR ligand discrimination, indicating coreceptor-mediated amplification of, or conversion to, catch-bonds.

Our findings highlight the importance of force in antigen recognition by the TCR and reveal that parameters derived from the bond profile, especially in the presence of coreceptor, are more informative predictors of T cell activation compared to conventional affinity-based measurements. These results offer insights into the relation between catch bonds and CD8 co-engagement in TCR antigen recognition.