The Solvent-Inaccessible Cys super(67) Residue of HLA-B27 Contributes to T Cell Recognition of HLA-B27/Peptide Complexes

Crystallographic studies have suggested that the cysteine at position 67 (Cys super(67)) in the B pocket of the MHC molecule HLA-B*2705 is of importance for peptide binding, and biophysical studies have documented altered thermodynamic stability of the molecule when Cys super(67) was mutated to seri...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2004-12, Vol.173 (11), p.6564-6573
Main Authors: Appel, Heiner, Kuon, Wolfgang, Kuhne, Maren, Huelsmeyer, Martin, Kollnberger, Simon, Kuhlmann, Stefanie, Weiss, Elisabeth, Zeitz, Martin, Wucherpfennig, Kai, Bowness, Paul, Sieper, Joachim
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Crystallographic studies have suggested that the cysteine at position 67 (Cys super(67)) in the B pocket of the MHC molecule HLA-B*2705 is of importance for peptide binding, and biophysical studies have documented altered thermodynamic stability of the molecule when Cys super(67) was mutated to serine (Ser super(67)). In this study, we used HLA-B27.Cys super(67) and HLA-B27.Ser super(67) tetramers with defined T cell epitopes to determine the contribution of this polymorphic, solvent-inaccessible MHC residue to T cell recognition. We generated these HLA- B27 tetramers using immunodominant viral peptides with high binding affinity to HLA-B27 and cartilage-derived peptides with lower affinity. We demonstrate that the yield of refolding of HLA-B27.Ser super(67) molecules was higher than for HLA- B27.Cys super(67) molecules and strongly dependent on the affinity of the peptide. T cell recognition did not differ between HLA-B27.Cys super(67) and HLA.B27.Ser super(67) tetramers for the viral peptides that were investigated. However, an aggrecan peptide-specific T cell line derived from an HLA-B27 transgenic BALB/c mouse bound significantly stronger to the HLA-B27.Cys super(67) tetramer than to the HLA- B27.Ser super(67) tetramer. Modeling studies of the molecular structure suggest the loss of a SH ... [pi] hydrogen bond with the Cysright arrowSer substitution in the HLA-B27 H chain which reduces the stability of the HLA-B27/peptide complex. These results demonstrate that a solvent-inaccessible residue in the B pocket of HLA-B27 can affect TCR binding in a peptide-dependent fashion.
ISSN:0022-1767