A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition
HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the alpha2 helix (B*4402 Asp156-->B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes sti...
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Published in | The Journal of experimental medicine Vol. 198; no. 5; pp. 679 - 691 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
The Rockefeller University Press
01.09.2003
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Subjects | |
Online Access | Get full text |
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Summary: | HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the alpha2 helix (B*4402 Asp156-->B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B*4402 and B*4403 share >95% of their peptide repertoire, B*4403 presents more unique peptides than B*4402, consistent with the stronger T cell alloreactivity observed toward B*4403 compared with B*4402. Crystal structures of B*4402 and B*4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B*4403 compared with B*4402. Thus, the polymorphism between HLA-B*4402 and B*4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this "minimal" mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Address correspondence to James McCluskey, Dept. of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia. Phone: 613-8344-5709; Fax: 613-9347-3226; email: jamesm1@unimelb.edu.au; or Jamie Rossjohn, The Protein Crystallography Unit, Dept. of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3168, Australia. Phone: 613-9905-3736; Fax: 613-9905-4699; email: Jamie.Rossjohn@med.monash.edu.au The online version of this article includes supplemental material. W.A. Macdonald and A.W. Purcell contributed equally to this work. Abbreviations used in this paper: H-bond, hydrogen bond; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; MS, mass spectrometry; RP, reverse phase; v.d.w., van der Waals. |
ISSN: | 0022-1007 1540-9538 |
DOI: | 10.1084/jem.20030066 |