Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity

Nat Immunol. 2016 Jan;17(1):87-94. doi: 10.1038/ni.3310. Epub 2015 Nov 2.


The T cell antigen receptor (TCR)-peptide-major histocompatibility complex (MHC) interface is composed of conserved and diverse regions, yet the relative contribution of each in shaping recognition by T cells remains unclear. Here we isolated cross-reactive peptides with limited homology, which allowed us to compare the structural properties of nine peptides for a single TCR-MHC pair. The TCR's cross-reactivity was rooted in highly similar recognition of an apical 'hot-spot' position in the peptide with tolerance of sequence variation at ancillary positions. Furthermore, we found a striking structural convergence onto a germline-mediated interaction between the TCR CDR1α region and the MHC α2 helix in twelve TCR-peptide-MHC complexes. Our studies suggest that TCR-MHC germline-mediated constraints, together with a focus on a small peptide hot spot, might place limits on peptide antigen cross-reactivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens / chemistry
  • Antigens / immunology*
  • Cross Reactions / immunology*
  • Crystallography, X-Ray
  • Humans
  • Lymphocyte Activation / immunology*
  • Major Histocompatibility Complex / immunology*
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / immunology
  • Protein Binding / immunology
  • Protein Conformation
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*


  • Antigens
  • Peptides
  • Receptors, Antigen, T-Cell, alpha-beta

Associated data

  • PDB/4MS8
  • PDB/4MVB
  • PDB/4MXQ
  • PDB/4N0C
  • PDB/4N5E