Recognition of Class II MHC Peptide Ligands That Contain β-Amino Acids

J Immunol. 2019 Sep 15;203(6):1619-1628. doi: 10.4049/jimmunol.1900536. Epub 2019 Aug 7.


Proteins are composed of α-amino acid residues. This consistency in backbone structure likely serves an important role in the display of an enormous diversity of peptides by class II MHC (MHC-II) products, which make contacts with main chain atoms of their peptide cargo. Peptides that contain residues with an extra carbon in the backbone (derived from β-amino acids) have biological properties that differ starkly from those of their conventional counterparts. How changes in the structure of the peptide backbone affect the loading of peptides onto MHC-II or recognition of the resulting complexes by TCRs has not been widely explored. We prepared a library of analogues of MHC-II-binding peptides derived from OVA, in which at least one α-amino acid residue was replaced with a homologous β-amino acid residue. The latter contain an extra methylene unit in the peptide backbone but retain the original side chain. We show that several of these α/β-peptides retain the ability to bind tightly to MHC-II, activate TCR signaling, and induce responses from T cells in mice. One α/β-peptide exhibited enhanced stability in the presence of an endosomal protease relative to the index peptide. Conjugation of this backbone-modified peptide to a camelid single-domain Ab fragment specific for MHC-II enhanced its biological activity. Our results suggest that backbone modification offers a method to modulate MHC binding and selectivity, T cell stimulatory capacity, and susceptibility to processing by proteases such as those found within endosomes where Ag processing occurs.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / metabolism*
  • Animals
  • Binding Sites / physiology
  • Cell Line, Tumor
  • Genes, MHC Class II / physiology
  • Histocompatibility Antigens Class II / metabolism*
  • Ligands
  • Mice
  • Peptide Fragments / metabolism
  • Protein Binding / physiology
  • Receptors, Antigen, T-Cell / metabolism
  • Structure-Activity Relationship
  • T-Lymphocytes / metabolism


  • Amino Acids
  • Histocompatibility Antigens Class II
  • Ligands
  • Peptide Fragments
  • Receptors, Antigen, T-Cell