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 ␣ 2 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 Ͼ 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.Key words: class I histocompatibility molecules • antigen presentation • crystallography • X-ray diffraction • graft rejection • polymorphism protective immunity against microbes (1-3). HLA alleles can differ from each other by only a single amino acid ("micropolymorphism") or by Ͼ 30 amino acids (4). It has been suggested that there are nine major HLA class I "supertypes," or clusters of alleles, that each possess a unique broad specificity for common anchor motifs in antigenic peptides (5). Alleles from each of these supertypic families are distributed in virtually all human populations and account

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

“…63 Since the HLA-B44 is the primary allotype contributing Bw4 ligand in HLA-A*29-positive subjects, the altered antigen-binding cleft may avoid its binding to inhibitory receptor KIR3DL1 as demonstrated with HLA-B*2705 molecules, 64 which in turn may further reduce inhibition and contribute to the increased NK and CTL activation.…”

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

“…Typically, these involve highly related allotypes that exhibit limited sequence differences, which nevertheless often result in biologically significant changes in conformation of the peptide and/or the MHC-I molecule (2,(61)(62)(63). In contrast, despite the comparatively low level of sequence identity between Qa-1 b and HLA-E, remarkably, they present their respective peptide cargoes in a very similar manner for recognition by CD94-NKG2 receptors.…”

“…There are a number of crystal structures of different MHC molecules binding the one peptide (2,60,61). Typically, these involve highly related allotypes that exhibit limited sequence differences, which nevertheless often result in biologically significant changes in conformation of the peptide and/or the MHC-I molecule (2,(61)(62)(63).…”

How an alloreactive T-cell receptor achieves peptide and MHC specificity

“…Beyond impacting peptide binding directly, polymorphisms within the binding groove are also likely to influence peptide conformation, detectable as an impact on TCR-binding affinity (33,34). We tested influences on conformation directly by examining position 152, which is a valine in A2 and B13, but a glutamate or tryptophan in the other A, B, C, and E proteins.…”