Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

Linda Wooldridge, Anya Lissina, Jonathan Vernazza, Emma Gostick, Bruno Laugel, Sarah L Hutchinson, Fareed Mirza, P Rod Dunbar, Jonathan M Boulter, Meir Glick, Vincenzo Cerundolo, Hugo A van den Berg, David A Price, Andrew K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

48 Citations (Scopus)

Abstract

CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.

Original languageEnglish
Pages (from-to)1323-33
Number of pages11
JournalEuropean Journal of Immunology
Volume37
Issue number5
DOIs
Publication statusPublished - May 2007

Keywords

  • Amino Acid Sequence
  • Antigen Presentation
  • Antigens, CD8
  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • HLA-A2 Antigen
  • Humans
  • Lymphocyte Activation
  • Molecular Sequence Data
  • Mutation
  • Protein Structure, Quaternary
  • Receptors, Antigen, T-Cell
  • Surface Plasmon Resonance
  • T-Lymphocytes, Cytotoxic
  • Transfection

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