A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition

• Published in: The Journal of experimental medicine Vol. 198; no. 5; pp. 679 - 691
• Main Authors: Macdonald, Whitney A, Purcell, Anthony W, Mifsud, Nicole A, Ely, Lauren K, Williams, David S, Chang, Linus, Gorman, Jeffrey J, Clements, Craig S, Kjer-Nielsen, Lars, Koelle, David M, Burrows, Scott R, Tait, Brian D, Holdsworth, Rhonda, Brooks, Andrew G, Lovrecz, George O, Lu, Louis, Rossjohn, Jamie, McCluskey, James
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 01.09.2003
• Subjects: Alleles; Cell Line; Crystallography, X-Ray; Cytokines - blood; Gene Frequency; HLA-B Antigens - chemistry; HLA-B Antigens - genetics; HLA-B44 Antigen; Humans; Lymphocyte Culture Test, Mixed; Models, Molecular; Protein Structure, Secondary; Sex Characteristics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T-Lymphocytes - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20030066

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.