Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes

J Am Chem Soc. 2021 May 5;143(17):6470-6481. doi: 10.1021/jacs.1c00016. Epub 2021 Apr 21.

Abstract

CD8+ T cells express T cell receptors (TCRs) that recognize short peptide antigens in the context of major histocompatibility class I (MHC I) molecules. This recognition process produces an array of cytokine-mediated signals that help to govern immunological responses. Design of biostable MHC I peptide vaccines containing unnatural subunits is desirable, and synthetic antigens in which a native α-amino acid residue is replaced by a homologous β-amino acid residue (native side chain but extended backbone) might be useful in this regard. We have evaluated the impact of α-to-β backbone modification at a single site on T cell-mediated recognition of six clinically important viral and tumor-associated antigens bound to an MHC I. Effects of this modification on MHC I affinity and T cell activation were measured. Many of these modifications diminish or prevent T cell response. However, a number of α/β-peptide antigens were found to mimic the activity of natural antigens or to enhance maximal T cell response, as measured by interferon-γ release. Results from this broad exploratory study advance our understanding of immunological responses to antigens bearing unnatural modifications and suggest that α/β-peptides could be a source of potent and proteolytically stable variants of native antigens.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • HLA-A2 Antigen / chemistry
  • HLA-A2 Antigen / immunology*
  • Humans
  • Lymphocyte Activation
  • Membrane Proteins / chemistry
  • Membrane Proteins / immunology
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / immunology
  • Protein Conformation, alpha-Helical
  • Structure-Activity Relationship
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / immunology

Substances

  • Antigens, Neoplasm
  • CTAG1B protein, human
  • HLA-A2 Antigen
  • Membrane Proteins
  • Peptides
  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa