International Immunology, Vol. 15, No. 5, pp. 565-576,
May 2003
© 2003 Japanese Society for Immunology
Functional analysis of HLA-DP polymorphism: a crucial role for DPß residues 9, 11, 35, 55, 56, 69 and 84–87 in T cell allorecognition and peptide binding
1 Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain 2 Department of Biology and Division of Respiratory Diseases of the University of ‘Tor Vergata’ at the IRCCS ‘L. Spallanzani’, 00149 Rome, Italy 3 Unitat d'Immunologia, Departamento de Biologia Cellular, Fisiologia e Immunologia. Institut de Biología Fundamental (UAB), 08193 Barcelona, Spain 4 Institute of Cell Biology, National Research Council, 00016 Monterotondo (Rome), Italy 5 Present address: Departamento de Microbiología y Genética, Instituto de Microbiología Bioquímica, USAL, 37007 Salamanca, Spain
Correspondence to: J. Arroyo; E-mail: jarroyo{at}farm.ucm.es
Transmitting editor: T. Sasazuki
The information available on the specific function of HLA-DP and the structure–function relationships is very limited. Here, single amino acid substitutions of HLA-DPB1*02012 have been used to analyze the role of polymorphic residues of the DPß1 domain on DP-mediated T cell allorecognition and peptide binding. Using a panel of specific anti-HLA-DP mAb, we identified the HLA-DP residues involved in the recognition by these mAb, with a crucial role for DPß56 for most of the mAb assayed. Individual substitutions at residues 9, 11, 35, 55, 56 and 69 completely abrogated T cell recognition mediated by two different HLA-DPw2-allospecific T cell clones (8.3 and 8.9). Interestingly single changes at positions 9, 11, 35 and 55 of HLA-DPß also altered the binding of peptides AAII(12–27) and IIP(53–65), natural ligands of the HLA-DPB1*02012 molecule. Individual changes at residues located in pocket 1 (84, 85, 86 and 87 from HLA-DPß) led to a partial reduction in cytotoxic T lymphocyte-mediated lysis and also partially affected peptide binding. However, the simultaneous substitution of these positions completely abolished both T cell allorecognition and peptide binding, suggesting a major role for polymorphisms at pocket 1 in HLA-DP function. Molecular modeling, used to predict changes induced by amino acid substitutions, supported the functional data. Taken together, these results strongly suggest that polymorphic residues 84, 85, 86 and 87 at pocket 1, residues 9, 35 and 55 at pocket 9, and residues 11 and 69 at pockets 6 and 4 respectively play a key role in HLA-DP function, probably by modifying the way the peptide is bound within the groove of HLA-DP2 and determining changes in the conformation of the MHC–peptide complex recognized by the TCR.
Keywords: allorecognition, HLA-DP antigen, molecular modeling, peptide binding, polymorphism, T cell
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