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The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α 3 domain of MHC I allosterically, resulting in enhanced peptide selector function.

Major histocompatibility complex class I (MHC-I) molecules play a key part in the adaptive immune response by presenting antigens to CD8 + T cells. The high degree of polymorphism in MHC-I leads to significant variation in their dependence on the components of the antigen processing and presentation pathway, such as the transporter associated with antigen processing (TAP) and tapasin, and their affinity for the peptide editor TAP-binding protein related (TAPBPR). Here, we investigated the influence of TAPBPR on the cell surface phenotype and peptide repertoire presented by two human leukocyte antigen (HLA) class I allotypes, HLA-B*44:02 and HLA-B*44:05, which are known to differ drastically in their dependence on tapasin. TAPBPR bound weakly to both HLA-B*44:02 and HLA-B*44:05. In contrast to tapasin depletion, the loss of TAPBPR has a limited effect on the cell surface expression of these two molecules. Analysis of the immunopeptidomes presented in the presence and absence of TAPBPR revealed that TAPBPR expression restricted the peptide repertoire presented on HLA-B*44:05, while it diversified the repertoire presented on HLA-B*44:02. Overall, TAPBPR improved the predicted affinity of the peptides displayed on both the HLA-B44 molecules. Furthermore, TAPBPR enhanced the presentation of peptides containing a C-terminal tryptophan residue. Our results show that TAPBPR can significantly impact the peptide repertoire of MHC-I molecules to which it binds weakly. Furthermore, this represents the first study that points to a role for TAPBPR in selecting a specific peptide sequence on MHC class I molecules.

Knowledge about the magnitude of individual polymorphism is a critical part in understanding the complexity of comprehensive mismatching. HLA-B*44:09 differs from the highly frequent HLA-B*44:02 allele by amino acid exchanges at residues 77, 80, 81, 82 and 83. We aimed to identify the magnitude of these mismatches on the features of HLA-B*44:09 bound peptides since residues 77, 80 and 81 comprise part of the F pocket which determines sequence specificity at the pΩ position of the peptide. Using soluble HLA technology we determined >200 individual (nonduplicate) self-peptides from HLA-B*44:09 and compared their features with that of the published peptide features of HLA-B*44:02. Both alleles illustrate an anchor motif of E at p2. In contrast to the C-terminal peptide binding motif of B*44:02 (W, F, Y or L), B*44:09-derived peptides are restricted predominantly to L or F. The source of peptides for both alleles is identical (LCL 721.221 cells) allowing us to identify 23 shared peptides. The majority of these peptides however contained the restricted B*44:09 anchor motif of F or L at the pΩ position. Molecular modelling based on the B*44:02 structure highlights that the differences of the C-terminal peptide anchor between both alleles can be explained primarily by the B*44:02 81Ala  > B*44:09 81Leu polymorphism which restricts the size of the amino acid that can be accommodated in the F pocket of B*44:09. These results highlight that every amino acid substitution has an impact of certain magnitude on the alleles function and demonstrate how surrounding residues orchestrate peptide specificity.

Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered to function as a series of \"independent pegs\" that either anchor the peptide (p) to the MHC-I and/or interact with the spectrum of αβ-T-cell receptors (TCRs) specific for the pMHC-I epitope in question. Mining of the extensive pMHC-I structural database established that many self- and viral peptides show extensive and direct interresidue interactions, an unexpected finding that has led us to the idea of \"constrained\" peptides. Mutational analysis of two constrained peptides (the HLA B44 restricted self-peptide (B44DPα-EEFGRAFSF) and an H2-Db restricted influenza peptide (DbPA, SSLENFRAYV) demonstrated that the conformation of the prominently exposed arginine in both peptides was governed by interactions with MHC-I-orientated flanking residues from the peptide itself. Using reverse genetics in a murine influenza model, we revealed that mutation of an MHC-I-orientated residue (SSLENFRAYV [rightward arrow] SSLENARAYV) within the constrained PA peptide resulted in a diminished cytotoxic T lymphocyte (CTL) response and the recruitment of a limited pMHC-I specific TCR repertoire. Interactions between individual peptide positions can thus impose fine control on the conformation of pMHC-I epitopes, whereas the perturbation of such constraints can lead to a previously unappreciated mechanism of viral escape.

Chronic spontaneous urticaria (CSU) is the most common form of chronic urticaria. A considerable amount of data supports an immunological basis for CSU. Some research has focused on the association between chronic urticaria and specific human leukocyte antigen (HLA) alleles. The aim of this study was to investigate the HLA status of Polish patients diagnosed with CSU. Methods: The standard complement-dependent microlymphocytotoxicity assay and PCR amplification with sequence-specific primers were used to analyze HLA alleles in 115 patients diagnosed with CSU, and the results were compared to those from 162 healthy, genetically unrelated individuals. Results: Among the HLA-A alleles, A-33 occurred significantly more often in the control group (p < 0.01). Analysis of the HLA-B allele frequencies revealed the prevalence of the B44 antigen in the study group (p < 0.0001). Frequencies of HLA-C alleles and HLA-DQ did not differ significantly between the groups. Among the HLA class II alleles, DRB1*04 was observed significantly more often in the study population (p < 0.001), mainly in the autoimmunological subtype of urticaria. Conclusion: HLA alleles may be involved in CSU development or play a protective role in CSU.

Bontkes et al's results indicate that the HLA-B44 genotype in conjunction with a down-regulated phenotype may influence rate of progression in cervical neoplasia presumably due to evasion of cellular immunity.

Herpes zoster is a common disease caused by reactivation of the varicella zoster virus (VZV). In a small number of herpes zoster patients, pain persists beyond 4 weeks or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). Positive associations of human histocompatibility leukocyte antigens (HLA) class I antigens, A33 and B44, with PHN in the Japanese population have been reported. Our hypothesis is that susceptibility genes to PHN might exist in the HLA region and the study objective is to further examine possible associations of genes in HLA class I, II and III regions, HLA - A , - B , - DRB1 , tumor necrosis factor α ( TNFA ) promoter , and a natural killer cell activating receptor, NKp30 polymorphisms with PHN. Although TNFA or NKp30 in the class III region had been considered as a candidate locus, we found no associations of TNFA promoter or NKp30 polymorphisms with PHN in this study. We demonstrated that HLA - A*3303 , - B*4403 and - DRB1*1302 alleles were significantly associated with PHN ( P =0.0007 for A*3303 , P =0.001 for B*4403 and P =0.001 for DRB1*1302 ). The frequency of the HLA - A*3303 - B*4403 - DRB1*1302 haplotype was also significantly higher in the PHN patients than in the healthy controls ( P =0.0039). Our results suggest that this haplotype might be related to the pathogenesis of PHN.