Atomistic TCR-ligand interactions instruct memory T-cell differentiation and crossreactivity

While memory T-cells provide protective immunity against specific pathogens, their post-encounter differentiation into central (TCM) and/or effector (TEM) subpopulations remains enigmatic. We thus explored the CD8 T-cell receptor (TCR) repertoire of 242 murine TCR clonotypes directed against an immunodominant influenza A virus (IAV) peptide/major histocompatibility complex (pMHC) ligand, the nucleoprotein NP366-374/Db, leveraging single-cell transcriptomics with paired TCR sequencing, mechanosensing metrics, and in vivo memory development plus TCR-pMHC structural analyses. Polar TEM and more variegated TCM repertoires as well as bipotential “bipolar” clonotypes (TBP) revealed weak force-dependent bonding parameters associated with heterosubtypic IAV crossreactivities. TCM and TEM polarities manifest pMHC binding skewed to TCR- versus TCR-subunit mechanotransduction, respectively, unlike the more signaling-balanced TBP TCRs. In sum, TCR diversity anticipates pathogen evolution whereas divergent signaling regulates memory fate.