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The Solvent-Inaccessible Cys⁶⁷ Residue of HLA-B27 Contributes to T Cell Recognition of HLA-B27/Peptide Complexes¹

Heiner Appel^2,3,*, Wolfgang Kuon^3,*, Maren Kuhne^*, Martin Hülsmeyer, Simon Kollnberger, Stefanie Kuhlmann^*, Elisabeth Weiss^¶, Martin Zeitz^*, Kai Wucherpfennig^||, Paul Bowness and Joachim Sieper^*,

^* Division of Gastroenterology, Infectiology and Rheumatology, Charité Berlin, Campus Benjamin Franklin, Institute for Chemistry/Crystallography, Free University Berlin, and Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany; Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; ^¶ Institute for Anthropology and Human Genetics, Ludwig-Maximillians-Universität Munich, Munich, Germany; and ^|| Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Department of Neurology, Harvard Medical School, Boston, MA 02115

Crystallographic studies have suggested that the cysteine at position 67 (Cys⁶⁷) 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 Cys⁶⁷ was mutated to serine (Ser⁶⁷). In this study, we used HLA-B27.Cys⁶⁷ and HLA-B27.Ser⁶⁷ 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.Ser⁶⁷ molecules was higher than for HLA-B27.Cys⁶⁷ molecules and strongly dependent on the affinity of the peptide. T cell recognition did not differ between HLA-B27.Cys⁶⁷ and HLA.B27.Ser⁶⁷ 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.Cys⁶⁷ tetramer than to the HLA-B27.Ser⁶⁷ tetramer. Modeling studies of the molecular structure suggest the loss of a SH ... hydrogen bond with the CysSer 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.

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The JI 2004 173: 6499-6500. [Full Text]  

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