A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition
AuthorMacdonald, WA; Purcell, AW; Misfud, NA; Ely, LK; Williams, DS; Chang, LN; Gorman, J; Clements, CS; Kjer-Nielsen, L; Koelle, DM; ...
Source TitleJOURNAL OF EXPERIMENTAL MEDICINE
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sPURCELL, ANTHONY; WILLIAMS, DAVID; Kjer-Nielsen, Lars; Tait, Brian; Brooks, Andrew; McCluskey, James; CHANG, LINUS; MACDONALD, WHITNEY ALISON; MIFSUD, NICOLE ANDREA
AffiliationMicrobiology And Immunology
Document TypeJournal Article
CitationsMacdonald, W. A., Purcell, A. W., Misfud, N. A., Ely, L. K., Williams, D. S., Chang, L. N., Gorman, J., Clements, C. S., Kjer-Nielsen, L., Koelle, D. M., Burrows, S. R., Tait, B. D., Holdsworth, R., Brooks, A. G., Lovrecz, G. O., Lu, L., Rossjohn, J. & McCluskey, J. (2003). A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition. JOURNAL OF EXPERIMENTAL MEDICINE, 198 (5), pp.679-691. https://doi.org/10.1084/jem.20030066.
Access StatusAccess this item via the Open Access location
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194191
C1 - Journal Articles Refereed
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.
KeywordsCellular Immunology; Immune System and Allergy
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