Secreted HLA recapitulates the immunopeptidome and allows in-depth coverage of HLA A*02:01 ligands

Scull, Katherine E.; Dudek, Nadine L.; Corbett, Alexandra J.; Ramarathinam, Sri H.; Gorasia, Dhana G.; Williamson, Nicholas A.; Purcell, Anthony W.

doi:10.1016/j.molimm.2012.02.117

Cited by 42 publications

(41 citation statements)

References 33 publications

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“…We found that 5% of the peptides were longer than 11 amino acids. This is in line with the results obtained by Scull et al for a smaller set of HLA-A2 peptides (7).…”

Section: Discussionsupporting

confidence: 93%

“…The frequency of cysteine in the Swissprot human database is 2%. Therefore, we calculate the chance that a peptide ligand will contain a cysteine residue as 15% and 13% for a 10-mer (1 Ϫ (0.98) 8 ϭ 0.15) and a 9-mer (1 Ϫ (0.98) 7 ϭ 0.13) ligand, respectively (we excluded the two anchor positions for this calculation because cysteine is not favorable at anchor positions). Nine percent of our peptides contained a cysteine residue.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, gene expression studies have shown many nonstandard, unexpected protein products, including the production of antigens derived from aberrant protein fragments as a result of expression in alternative reading frames (6). Several studies report the identification of HLA ligands (7)(8)(9)(10). Many results have been collected and discussed in a recent review on the large-scale analysis of HLA class I ligands (11).…”

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confidence: 99%

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The Human Leukocyte Antigen–presented Ligandome of B Lymphocytes

Hassan

Kester

et al. 2013

Molecular & Cellular Proteomics

116

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The presented HLA class I ligands are the products of the intracellular processing machinery, with its continuous cycle of protein synthesis and degradation (3). Much is known about the proteins involved in antigen processing, but high fidelity ligand/epitope predictions are at present not possible. The discovery of additional involved enzymes (3, 4) and the exciting discovery of peptide splicing (5) have shown that antigen processing is even more complex than was previously thought. Moreover, gene expression studies have shown many nonstandard, unexpected protein products, including the production of antigens derived from aberrant protein fragments as a result of expression in alternative reading frames (6). Several studies report the identification of HLA ligands (7-10). Many results have been collected and discussed in a recent review on the large-scale analysis of HLA class I ligands (11). Collectively, these reports illustrate the need for in-depth elucidation of the HLA ligandome.Elucidation of T cell epitopes has traditionally been achieved with the use of a forward immunological approach, as pioneered by Hunt and coworkers (12,13). In this approach, the cognate peptide of T cells with the appropriate activity profile is elucidated via repeated rounds of chromatographic separation in combination with T cell recognition assays. Because T cells are not always available from the start, reverse immunological approaches (14 -17) have been developed to predict T cell epitopes through a combination of bioinformatics and in vitro proteasome digests. Predicted epitopes are synthesized and tested for their capability to activate T cells. The main disadvantage of this approach is that less than 0.1% of the peptides that survive intracellular processing are presented on HLA class I molecules (3).Therefore, we developed a large-scale peptidomics approach that is a reverse immunology approach based not on From the ‡Department of Immunohematology and Blood Transfusion,

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“…We found that 5% of the peptides were longer than 11 amino acids. This is in line with the results obtained by Scull et al for a smaller set of HLA-A2 peptides (7).…”

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Human Leukocyte Antigen–presented Ligandome of B Lymphocytes

Hassan

Kester

et al. 2013

Molecular & Cellular Proteomics

116

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“…The prevalence of leucine at PV is observed in many human and murine class I peptides but the bias for proline is less common (28,29,33,(44)(45)(46)(47). We compared the frequency of proline at PV in bat class I peptides to peptides presented by various human and murine class I alleles.…”

Section: Comparison Of C-terminal Amino Acid Biases and Ag-binding CLmentioning

confidence: 99%

Characterization of the Antigen Processing Machinery and Endogenous Peptide Presentation of a Bat MHC Class I Molecule

Wynne

Woon

Dudek

et al. 2016

The Journal of Immunology

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Bats are a major reservoir of emerging and re-emerging infectious diseases, including severe acute respiratory syndrome–like coronaviruses, henipaviruses, and Ebola virus. Although highly pathogenic to their spillover hosts, bats harbor these viruses, and a large number of other viruses, with little or no clinical signs of disease. How bats asymptomatically coexist with these viruses is unknown. In particular, little is known about bat adaptive immunity, and the presence of functional MHC molecules is mostly inferred from recently described genomes. In this study, we used an affinity purification/mass spectrometry approach to demonstrate that a bat MHC class I molecule, Ptal-N*01:01, binds antigenic peptides and associates with peptide-loading complex components. We identified several bat MHC class I–binding partners, including calnexin, calreticulin, protein disulfide isomerase A3, tapasin, TAP1, and TAP2. Additionally, endogenous peptide ligands isolated from Ptal-N*01:01 displayed a relatively broad length distribution and an unusual preference for a C-terminal proline residue. Finally, we demonstrate that this preference for C-terminal proline residues was observed in Hendra virus–derived peptides presented by Ptal-N*01:01 on the surface of infected cells. To our knowledge, this is the first study to identify endogenous and viral MHC class I ligands for any bat species and, as such, provides an important avenue for monitoring and development of vaccines against major bat-borne viruses both in the reservoir and spillover hosts. Additionally, it will provide a foundation to understand the role of adaptive immunity in bat antiviral responses.

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“…Lysates were cleared by ultracentrifugation (180,000 x g) and HLA-peptide complexes sequentially immunoaffinity purified using solid-phase bound anti-Bw6 (HB152-SRF) antibodies. Bound complexes were washed and peptides eluted by acidification with 10 % acetic acid, as described [15][16][17]. The mixture of peptides and HLA proteins was fractionated on a 4.6 mm internal diameter x 50 mm long monolithic reversed-phase C18 HPLC column (Chromolith Speed Rod, Merck) using an ÄKTAmicro™ HPLC system (GE Healthcare).…”

Section: Purification Of Mhc-bound Peptidesmentioning

confidence: 99%

The adaptive immune response to Epstein-Barr virus

Rist

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School of Medicine iiMajor histocompatibility complex (MHC) class I molecules form medleys with peptide antigens which are expressed on the cell surface for recognition by CD8 + T cells. Derived from antigens synthesized in the cytoplasm, these peptides are generally 8-10 amino acids in length. For most MHC alleles two of the pockets within the peptide binding groove display a marked preference for one or two amino acids at certain anchor positions within the peptide. This was the breakthrough discovery that enabled more efficient CTL epitope mapping. Dependent on this information, web-based algorithms used to predict CD8 + T cell epitopes were designed to include peptides limited to between 8 and 10 residues. The apparent dominance of MHC class I peptides of 8 to 10 amino acids in length may be misleading and result from this bias of widely used

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Secreted HLA recapitulates the immunopeptidome and allows in-depth coverage of HLA A*02:01 ligands

Cited by 42 publications

References 33 publications

The Human Leukocyte Antigen–presented Ligandome of B Lymphocytes

The Human Leukocyte Antigen–presented Ligandome of B Lymphocytes

Characterization of the Antigen Processing Machinery and Endogenous Peptide Presentation of a Bat MHC Class I Molecule

The adaptive immune response to Epstein-Barr virus

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