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

Nat Immunol. 2022 Mar;23(3):446-457. doi: 10.1038/s41590-022-01129-x. Epub 2022 Feb 17.


T cells acquire a regulatory phenotype when their T cell antigen 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 (Treg) 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 conventional T cell (Tconv) phenotype through expansion. To elucidate drivers of these predictive TCR features, we then examined the two elements of the Treg TCR ligand separately: the self-peptide and the human MHC class 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 class II-restricted activation.

MeSH terms

  • Cell Lineage
  • Complementarity Determining Regions / genetics
  • Peptides
  • Receptors, Antigen, T-Cell*
  • Receptors, Antigen, T-Cell, alpha-beta* / genetics
  • T-Lymphocytes, Regulatory


  • Complementarity Determining Regions
  • Peptides
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta