HLA Class I Binding Motifs Derived from Random Peptide Libraries Differ at the COOH Terminus from Those of Eluted Peptides

Davenport, Miles P.; Smith, Katherine J.; Barouch, Dan H.; Reid, S. W. J.; Bodnar, Wanda M.; Willis, Anthony C.; Hunt, Donald F.; Hill, Adrian V. S.

doi:10.1084/jem.185.2.367

Cited by 45 publications

(17 citation statements)

References 19 publications

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“…In contrast, we observed several differences to HLA-peptidebinding studies [5] where Gly was found among the preferred amino acids at the C-terminus of the peptides: none of our 121 HLA-BÃ1801-presented ligands showed a Gly in PO. Such discrepancies between analysis of natural ligands and binding studies have already been reported [24]. Mere binding to a certain HLA molecule is not sufficient for natural presentation since critical steps of antigen processing other than HLA binding (such as proteolytic activities and specificities as well as transport preferences) do play a major role.…”

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confidence: 92%

Essential differences in ligand presentation and T cell epitope recognition among HLA molecules of the HLA‐B44 supertype

et al. 2008

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Human leukocyte antigens (HLA) have long been grouped into supertypes to facilitate peptide-based immunotherapy. Analysis of several hundreds of peptides presented by all nine antigens of the HLA-B44 supertype (HLA-B*18, B*37, B*40, B*41, B*44, B*45, B*47, B*49 and B*50) revealed unique peptide motifs for each of them. Taking all supertype members into consideration only 25 out of 670 natural ligands were found on more than one HLA molecule. Further direct comparisons by two mass spectrometric methods -isotope labeling as well as a label-free approach -consistently demonstrated only minute overlaps of below 3% between the ligandomes of different HLA antigens. In addition, T cell reactions of healthy donors against immunodominant HLA-B*44 and HLA-B*40 epitopes from EBV lacked promiscuous T-cell recognition within the HLA-B44 supertype. Taken together, these results challenge the common paradigm of broadly presented epitopes within this supertype.Key words: Antigen presentation/processing . CD8 T cells . Immunotherapy . Mass spectrometry . MHC Supporting Information available online IntroductionPeptides presented on human leukocyte antigen (HLA) class I molecules are the final result of antigen processing and are usually generated under the participation of the cytosolic proteasomes and aminopeptidases. About 1% of peptides produced in the cytosol are translocated to the ER via TAP [1].Upon undergoing further N-terminal trimming, the peptides are finally loaded onto HLA class I molecules. Thus, peptides presented on the cell surface have succeeded in following various rules along the pathway of antigen processing. They are determined by the cleavage specificities of the proteasome and by cytosolic aminopeptidase activity. The transport via TAP shows strong preferences for hydrophobic or charged residues in both the C-terminal and the second position [2]. Selectivity also applies to trimming, as peptide bonds between any amino acid and Pro cannot be cleaved by peptidases of the ER, and HLA class I molecules themselves serve as templates for their to-be-ligands Eur. J. Immunol. 2008. 38: 2993-3003 DOI 10.1002 Antigen processing 2993 [3]. Finally, peptides build stable complexes with HLA molecules only if they fit into the binding groove, which depends on the nature of the so-called pockets. The allele-specific amino acid composition of these pockets determines both their polarity and stereochemistry and, consequently, also the residues of the peptide that are allowed to protrude into these pockets. The peptide motif describes such primary anchors of the peptide, which have the strongest effect on ligand binding as well as less constricted but still nonetheless important auxiliary anchors. The extensive polymorphism of HLA genes provides the basis for similar variability among peptide motifs. With an increasing number of HLA alleles characterized in more detail these were classified into several groups. So-called supertypes can be defined according to either structure or function [4]. The latter approach groups HLA ...

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Essential differences in ligand presentation and T cell epitope recognition among HLA molecules of the HLA‐B44 supertype

et al. 2008

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“…We addressed this issue by generating recombinant soluble T18 d H chain molecules in E. coli and refolding this protein with ␤ 2 m in the presence or absence of a fully random nonameric peptide library containing all natural amino acids except Cys. This approach was successfully used to investigate the peptide binding motif of another class Ib molecule, Qa-1 (24), in addition to class Ia molecules (33,34). In Fig.…”

Section: T18 D Folds Efficiently With ␤ 2 M In the Absence Of Peptidementioning

confidence: 99%

Peptide-Independent Folding and CD8αα Binding by the Nonclassical Class I Molecule, Thymic Leukemia Antigen

Weber¹,

Attinger

Kemball³

et al. 2002

The Journal of Immunology

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The nonclassical class I molecule, thymic leukemia (TL), has been shown to be expressed on intestinal epithelial cells and to interact with CD8+ intraepithelial T lymphocytes. We generated recombinant soluble TL (T18d) H chains in bacteria as inclusion bodies and refolded them with β2-microglobulin in the presence or absence of a random peptide library. Using a mAb, HD168, that recognizes a conformational epitope on native TL molecules, we observed that protein folds efficiently in the absence of peptide. Circular dichroism analysis demonstrated that TL molecules have structural features similar to classical class I molecules. Moreover, thermal denaturation experiments indicated that the melting temperature for peptide-free TL is similar to values reported previously for conventional class I-peptide complexes. Our results also show that CD8αα binding is not dependent on either TL-associated peptide or TL glycosylation.

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“…BIMAS underestimated the activity of peptide GKLGFVFTL (experimental log T 1/2 : 3.176; BIMAS: 0.745; COMBINE: 2.778) and overestimated that of peptide GLGGGGFGV (experimental log T 1/2 : 0.903; BIMAS: 2.606; COMBINE: 1.651). For high activity (large log T 1/2 value in this study), the identity of the second amino acid residue of the HLA-A2 epitope peptide has been reported to have a Leu or an Ile residue [21][22][23]. Peptide GKLGFVFTL (see above) displays high activity even though its second residue is a Lys (K), a topology that does not meet the preference criteria mentioned above.…”

Section: Resultsmentioning

confidence: 99%

An Interaction-based Approach for Affinity Prediction between Antigen Peptide and Human Leukocyte Antigen Using COMBINE Analysis

Nakamura

Ohmura

Nakanishi

2017

CBIJ

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In peptide vaccine therapy, a peptide with high affinity for human leukocyte antigen (HLA), is important to stimulate the immune system to kill cancer cells. Several methods to predict HLA-peptide binding have been reported, but most of them rely on informatics to analyze the amino acid sequence of the peptide. Although intermolecular-interaction-based analysis is expected to improve prediction accuracy, such a method generally involves a high computational cost. Therefore, comparative binding energy (COMBINE) analysis, a 3D-quantitative structure-activity relationship method, combined with a rapidly implemented protein modeling method, was applied to solve this problem. The new method enabled quick evaluation of peptide affinity predictions with accuracy beyond a statistical method. In addition, several amino acid residues of HLA, which are known to be important for peptide binding, could be identified.

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HLA Class I Binding Motifs Derived from Random Peptide Libraries Differ at the COOH Terminus from Those of Eluted Peptides

Cited by 45 publications

References 19 publications

Essential differences in ligand presentation and T cell epitope recognition among HLA molecules of the HLA‐B44 supertype

Essential differences in ligand presentation and T cell epitope recognition among HLA molecules of the HLA‐B44 supertype

Peptide-Independent Folding and CD8αα Binding by the Nonclassical Class I Molecule, Thymic Leukemia Antigen

An Interaction-based Approach for Affinity Prediction between Antigen Peptide and Human Leukocyte Antigen Using COMBINE Analysis

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