Constraints within major histocompatibility complex class I restricted peptides: presentation and consequences for T-cell recognition

Alexander Theodossis, Carole Guillonneau, Andrew David Welland, Lauren Kate Ely, Craig Steven Clements, Nicholas A Williamson, Andrew I Webb, Jacqueline Anne Wilce, Roger J Mulder, Michelle Anne Dunstone, Peter C Doherty, James McCluskey, Anthony Wayne Purcell, Stephen J Turner, Jamie Rossjohn

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47 Citations (Scopus)

Abstract

Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered to function as a series of independent pegs that either anchor the peptide (p) to the MHC-I and/or interact with the spectrum of alphabeta-T-cell receptors (TCRs) specific for the pMHC-I epitope in question. Mining of the extensive pMHC-I structural database established that many self- and viral peptides show extensive and direct interresidue interactions, an unexpected finding that has led us to the idea of constrained peptides. Mutational analysis of two constrained peptides (the HLA B44 restricted self-peptide (B44DPalpha-EEFGRAFSF) and an H2-D(b) restricted influenza peptide (D(b)PA, SSLENFRAYV) demonstrated that the conformation of the prominently exposed arginine in both peptides was governed by interactions with MHC-I-orientated flanking residues from the peptide itself. Using reverse genetics in a murine influenza model, we revealed that mutation of an MHC-I-orientated residue (SSLENFRAYV --> SSLENARAYV) within the constrained PA peptide resulted in a diminished cytotoxic T lymphocyte (CTL) response and the recruitment of a limited pMHC-I specific TCR repertoire. Interactions between individual peptide positions can thus impose fine control on the conformation of pMHC-I epitopes, whereas the perturbation of such constraints can lead to a previously unappreciated mechanism of viral escape.
Original languageEnglish
Pages (from-to)5534 - 5539
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number12
DOIs
Publication statusPublished - 2010

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