Repertoire analyses reveal T cell receptor sequence features that influence T cell fate

T cells acquire a regulatory phenotype when their T cell receptors (TCRs) experience an intermediate-to-high affinity interaction with a self-peptide presented via the major histocompatibility complex (MHC). Using TCRβ sequences from flow-sorted human cells, we identified TCR features that promote regulatory T cell (T(reg)) fate. From these results, we developed a scoring system to quantify TCR-intrinsic regulatory potential (TiRP). When applied to the tumor microenvironment, TiRP scoring helped to explain why only some T cell clones maintained the T(conv) phenotype through expansion. To elucidate drivers of these predictive TCR features, we then examined the two elements of the T(reg) TCR ligand separately: the self-peptide, and the human MHC II molecule. These analyses revealed that hydrophobicity in the third complementarity determining region (CDR3β) of the TCR promotes reactivity to self-peptides, while TCR variable gene (TRBV gene) usage shapes the TCR’s general propensity for human MHC II-restricted activation.