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

HLA-B4402 and B4403 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 (B4402 Asp156-->B4403 Leu156). CTLs discriminate between HLA-B4402 and B4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B4402 and B4403 share >95% of their peptide repertoire, B4403 presents more unique peptides than B4402, consistent with the stronger T cell alloreactivity observed toward B4403 compared with B4402. Crystal structures of B4402 and B4403 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 B4403 compared with B4402. Thus, the polymorphism between HLA-B4402 and B4403 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.