Open AccessRepertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate
Author(s) -
Kaitlyn A. Lagattuta,
Je-Won Kang,
Aparthan,
Kristen E. Pauken,
Anna Helena Jonsson,
Deepak A. Rao,
Arlene H. Sharpe,
Kazuyoshi Ishigaki,
Soumya Raychaudhuri
Publication year - 2022
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-022-01129-x
Subject(s) - t cell receptor , major histocompatibility complex , biology , t cell , antigen , complementarity determining region , microbiology and biotechnology , mhc restriction , phenotype , cytotoxic t cell , receptor , immunology , gene , genetics , peptide sequence , immune system , in vitro
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 (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 conventional T cell (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 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.