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
HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.
Transthyretin, a protein synthesized and secreted by the choroid plexus and liver, binds thyroid hormones in extracellular compartments. This binding prevents accumulation of thyroid hormones in the lipids of membranes, establishing extracellular thyroid hormone pools for the distribution of the hormones throughout the body and brain. The N-termini of the transthyretin subunits are longer and more hydrophobic in chicken than in eutherian transthyretins. Here, we show that this is a general structural feature of avian transthyretins. Systematic changes of protein structure during evolution result from selection pressure leading to changes in function. The evolution of transthyretin function, namely, the binding of thyroid hormones, was studied in nine vertebrate species. The affinity of thyroxine binding to transthyretin is lowest in avians (mean K d of about 30 nm), intermediate in metatherians (mean K d of about 17 nm) and highest in eutherians (mean K d of about 11 nm). The affinity for 3,5,3Htriiodothyronine shows an opposite trend, being four times higher for avian transthyretins than for mammalian transthyretins.
NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult somatic tissue, making it an ideal cancer vaccine candidate. Peptides derived from NY-ESO-1 have shown preclinical and clinical trial promise; however, biochemical features of these peptides have complicated their formulation and led to heterogeneous immune responses. We have taken a rational approach to engineer an HLA A2-restricted NY-ESO-1-derived T cell epitope with improved formulation and immunogenicity to the wild type peptide. To accomplish this, we have solved the x-ray crystallographic structures of HLA A2 complexed to NY-ESO (157-165) and two analogues of this peptide in which the C-terminal cysteine residue has been substituted to alanine or serine. Substitution of cysteine by serine maintained peptide conformation yet reduced complex stability, resulting in poor cytotoxic T lymphocyte recognition. Conversely, substitution with alanine maintained complex stability and cytotoxic T lymphocyte recognition. Based on the structures of the three HLA A2 complexes, we incorporated 2-aminoisobutyric acid, an isostereomer of cysteine, into the epitope. This analogue is impervious to oxidative damage, cysteinylation, and dimerization of the peptide epitope upon formulation that is characteristic of the wild type peptide. Therefore, this approach has yielded a potential therapeutic molecule that satiates the hydrophobic F pocket of HLA A2 and exhibited superior immunogenicity relative to the wild type peptide.Class I major histocompatibility complex (MHC) 1 molecules play a crucial role in immune surveillance by selectively binding to intracellular peptide antigens (Ag) and presenting them at the cell surface to CD8 ϩ T lymphocytes (T CD8 ), including cytotoxic T lymphocytes (CTL). Eradication of tumors is associated with a robust cytotoxic T cell response to antigens expressed by the tumor (tumor-associated antigens (TAA)). Because many TAA are self-proteins or closely related to selfproteins, they tend to be poorly immunogenic (1-5). Moreover, many TAA-derived peptides are not strong binders to class I molecules, making strategies that revolve around tumor Ag delivery poor inducers of CD8 T cell immunity (6). Synthetic peptide-based vaccines offer a flexible, relatively simple and cost-effective way to treat a variety of human diseases, including the immunotherapy of cancer. Moreover, synthetic peptides are easily engineered to improve the efficacy of the immunogen. Such engineering may include optimizing target MHC class I binding by substituting key residues with more appropriate anchor residues. In addition, peptide-based therapeutics can be engineered to improve formulation and storage properties, and strategies exist to protect labile peptide bonds by incorporating nonpeptidic structures (7-11). Several studies have incorporated nonnatural amino acids in peptidic structures to improve compound stability and maintain T cell cross-reactivity. For example, some studie...
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