title: A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition.
abstract: 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.
authors.affiliation: Dept. of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Macdonald
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mifsud
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Ely
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Linus
authors.initials: L
authors.lastname: Chang
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gorman
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Brian D
authors.initials: BD
authors.lastname: Tait
authors.forename: Rhonda
authors.initials: R
authors.lastname: Holdsworth
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: George O
authors.initials: GO
authors.lastname: Lovrecz
authors.forename: Louis
authors.initials: L
authors.lastname: Lu
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D000483:Alleles; D002460:Cell Line; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000097:blood; D005787:Gene Frequency; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics*; D059948:HLA-B44 Antigen; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012727:Sex Characteristics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen