Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire

Nat Commun. 2019 Mar 4;10(1):1019. doi: 10.1038/s41467-019-08906-7.

Abstract

The αβ T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficient mouse strains, and find that MHC-restricted and MHC-independent TCRs are primarily distinguished by features in their non-germline CDR3 regions, with many pre-selection CDR3 sequences not compatible with MHC-binding. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR is restricted by both CDR3 length and specific amino acid usage. MHC-restriction disfavors TCR with CDR3 longer than 13 amino acids, limits positively charged and hydrophobic amino acids in CDR3β, and clonally deletes TCRs with cysteines in their CDR3 peptide-binding regions. Together, these MHC-imposed structural constraints form the basis to shape VDJ recombination sequences into MHC-restricted repertoires.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Complementarity Determining Regions / chemistry*
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology*
  • Lymphocyte Activation
  • Major Histocompatibility Complex / genetics
  • Major Histocompatibility Complex / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Sequence Analysis, Protein
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Thymus Gland / immunology*
  • V(D)J Recombination

Substances

  • Complementarity Determining Regions
  • Receptors, Antigen, T-Cell