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Abrogation of CTL epitope processing by single amino acid substitution flanking the C-terminal proteasome cleavage

N J Beekman1, P A van Veelen, T van Hall

  • 1Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands.

Journal of Immunology (Baltimore, Md. : 1950)
|February 5, 2000
PubMed

Insights

Cytotoxic T-lymphocyte (CTL) responses against Moloney murine leukemia virus (MuLV) tumor cells fail against Friend MuLV due to impaired epitope processing. A single amino acid change prevents proper proteasome cleavage, hindering CTL recognition.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Cytotoxic T-lymphocytes (CTLs) are crucial for anti-viral immunity.
  • Murine leukemia viruses (MuLVs) can induce tumors, eliciting CTL responses.
  • Recognition of tumor cells by CTLs depends on proper antigen processing and presentation.

Purpose of the Study:

  • To investigate why CTLs recognizing Moloney MuLV epitopes do not recognize Friend MuLV-transformed cells.
  • To elucidate the molecular mechanisms underlying the failure of CTL recognition of Friend MuLV tumor cells.

Main Methods:

  • Proteasome-mediated digestion analysis of synthetic viral peptides.
  • Analysis of peptide translocation by the transporter associated with antigen processing (TAP).
  • Assessment of peptide binding affinity to MHC class I molecules.

Main Results:

  • A single amino acid substitution (N-->D) flanking the C-terminal anchor residue in the Friend MuLV epitope impairs proteasome cleavage.
  • Proteasome cleavage of the Friend MuLV peptide occurs C-terminal to aspartic acid, not the correct C-terminal anchor residue.
  • Improperly processed Friend MuLV epitope fragments show reduced TAP translocation and MHC class I binding.

Conclusions:

  • Failure to recognize Friend MuLV-transformed tumor cells is due to a defect in proteasome-mediated processing of the CTL epitope.
  • A naturally occurring flanking aspartic acid residue in the Friend MuLV epitope prevents correct C-terminal cleavage, hindering antigen presentation.
  • This represents a novel mechanism by which viruses can evade CTL-mediated immune surveillance by subverting antigen processing.

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