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High peptide affinity for MHC class I does not correlate with immunodominance
A Müllbacher1, M Lobigs, J W Yewdell
1Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, A.C.T. 2601, Australia.
Scandinavian Journal of Immunology
|October 16, 1999
Summary
Cytotoxic T-cell responses to influenza are mainly against nucleoprotein (NP). A single amino acid change in MHC molecules (Kdm) significantly reduced lysis, suggesting T-cell receptor repertoire skewing, not high peptide affinity, drives immunodominance.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Cytotoxic T (Tc) cells are crucial for controlling viral infections like influenza.
- The immunodominance of specific viral epitopes in Tc-cell responses is a key aspect of adaptive immunity.
Purpose of the Study:
- To investigate the role of peptide binding groove structure in major histocompatibility complex (MHC) class I molecules on Tc-cell recognition.
- To determine whether high peptide affinity or T-cell receptor repertoire skewing dictates immunodominance in anti-influenza responses.
Main Methods:
- Used recombinant vaccinia viruses encoding wild-type (Kdw) and mutant (Kdm) MHC class I molecules.
- Assessed lysis of target cells expressing Kdw or Kdm by influenza-specific Tc cells.
- Investigated peptide binding and expression levels using synthetic peptides and co-infections.
Main Results:
- MHC Kdm molecules showed significantly reduced lysis of influenza-infected target cells compared to Kdw.
- Restoring peptide levels on Kdm-expressing cells rescued lysis, indicating a quantitative defect in complex formation.
- Influenza hemagglutinin peptides demonstrated higher affinity for Kdw than the nucleoprotein peptide.
Conclusions:
- The immunodominance of the influenza nucleoprotein peptide is likely due to T-cell receptor repertoire skewing, not inherently high peptide-MHC affinity.
- MHC molecule structure plays a critical role in the quantitative presentation of viral peptides to Tc cells.