, Volume 71, Issue 7, pp 445–454 | Cite as

Improved peptide-MHC class II interaction prediction through integration of eluted ligand and peptide affinity data

  • Christian GardeEmail author
  • Sri H. Ramarathinam
  • Emma C. Jappe
  • Morten Nielsen
  • Jens V. Kringelum
  • Thomas Trolle
  • Anthony W. PurcellEmail author
Original Article


Major histocompatibility complex (MHC) class II antigen presentation is a key component in eliciting a CD4+ T cell response. Precise prediction of peptide-MHC (pMHC) interactions has thus become a cornerstone in defining epitope candidates for rational vaccine design. Current pMHC prediction tools have, so far, primarily focused on inference from in vitro binding affinity. In the current study, we collate a large set of MHC class II eluted ligands generated by mass spectrometry to guide the prediction of MHC class II antigen presentation. We demonstrate that models developed on eluted ligands outperform those developed on pMHC binding affinity data. The predictive performance can be further enhanced by combining the eluted ligand and pMHC affinity data in a single prediction model. Furthermore, by including ligand data, the peptide length preference of MHC class II can be accurately learned by the prediction model. Finally, we demonstrate that our model significantly outperforms the current state-of-the-art prediction method, NetMHCIIpan, on an external dataset of eluted ligands and appears superior in identifying CD4+ T cell epitopes.


MHC class II Ligand prediction CD4+ epitope Pan method Machine learning Mass spectrometry Peptidomics 



ECJ was supported by a PhD stipend from the Innovation Fund Denmark. AWP was supported by a Principal Research Fellowship and project grant 1022509 from the National Health and Medical Research Council of Australia (NHMRC). SHR was supported by an Australian Postgraduate Award. MN is a researcher at the Argentinean National Research Council (CONICET).

We are grateful to the members of Prof. Purcell’s lab for their assistance in compiling the eluted ligand data. Furthermore, we thank the bioinformatics team at Evaxion Biotech for constructive feedback.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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ESM 1 (DOCX 1026 kb)
251_2019_1122_MOESM2_ESM.xls (3.3 mb)
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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christian Garde
    • 1
    Email author
  • Sri H. Ramarathinam
    • 2
  • Emma C. Jappe
    • 1
    • 3
  • Morten Nielsen
    • 3
    • 4
  • Jens V. Kringelum
    • 1
  • Thomas Trolle
    • 1
  • Anthony W. Purcell
    • 2
    Email author
  1. 1.Evaxion BiotechCopenhagenDenmark
  2. 2.Department of Biochemistry and Molecular Biology & Infection and Immunity Program, Biomedicine Discovery InstituteMonash UniversityClaytonAustralia
  3. 3.Department of Bio and Health InformaticsTechnical University of DenmarkLyngbyDenmark
  4. 4.Instituto de Investigaciones BiotecnológicasUniversidad Nacional de San MartínBuenos AiresArgentina

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