4.6 Article

Comparison of HLA ligand elution data and binding predictions reveals varying prediction performance for the multiple motifs recognized by HLA-DQ2.5

期刊

IMMUNOLOGY
卷 162, 期 2, 页码 235-247

出版社

WILEY
DOI: 10.1111/imm.13279

关键词

binding motif; binding predictions; ligand elution; MHC

资金

  1. National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R21AI134127, 75N93019C00001]
  2. National Institute of Dental and Craniofacial Research
  3. National Cancer Institute [U01DE028227]
  4. Bristol-Myers Squibb Company

向作者/读者索取更多资源

Binding prediction tools are commonly used in identifying peptides presented on MHC class II molecules, but discrepancies between ligand elution data and binding predictions have been reported. While most MHC class II eluted ligands are predicted to bind with high affinity, there are instances where an increased number of ligands not predicted to bind were found due to ambiguous MHC restrictions. Additional analyses also showed that ligands predicted to not bind may bind other co-expressed MHC class II molecules.
Binding prediction tools are commonly used to identify peptides presented on MHC class II molecules. Recently, a wealth of data in the form of naturally eluted ligands has become available and discrepancies between ligand elution data and binding predictions have been reported. Quantitative metrics for such comparisons are currently lacking. In this study, we assessed how efficiently MHC class II binding predictions can identify naturally eluted peptides, and investigated instances with discrepancies between the two methods in detail. We found that, in general, MHC class II eluted ligands are predicted to bind to their reported restriction element with high affinity. But, for several studies reporting an increased number of ligands that were not predicted to bind, we found that the reported MHC restriction was ambiguous. Additional analyses determined that most of the ligands predicted to not bind, are predicted to bind other co-expressed MHC class II molecules. For selected alleles, we addressed discrepancies between elution data and binding predictions by experimental measurements and found that predicted and measured affinities correlate well. For DQA1*05:01/DQB1*02:01 (DQ2.5) however, binding predictions did miss several peptides that were determined experimentally to be binders. For these peptides and several known DQ2.5 binders, we determined key residues for conferring DQ2.5 binding capacity, which revealed that DQ2.5 utilizes two different binding motifs, of which only one is predicted effectively. These findings have important implications for the interpretation of ligand elution data and for the improvement of MHC class II binding predictions.

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