Machine learning predictions of MHC-II specificities reveal alternative binding mode of class II epitopes

Immunity. 2023 Jun 13;56(6):1359-1375.e13. doi: 10.1016/j.immuni.2023.03.009. Epub 2023 Apr 5.


CD4+ T cells orchestrate the adaptive immune response against pathogens and cancer by recognizing epitopes presented on class II major histocompatibility complex (MHC-II) molecules. The high polymorphism of MHC-II genes represents an important hurdle toward accurate prediction and identification of CD4+ T cell epitopes. Here we collected and curated a dataset of 627,013 unique MHC-II ligands identified by mass spectrometry. This enabled us to precisely determine the binding motifs of 88 MHC-II alleles across humans, mice, cattle, and chickens. Analysis of these binding specificities combined with X-ray crystallography refined our understanding of the molecular determinants of MHC-II motifs and revealed a widespread reverse-binding mode in HLA-DP ligands. We then developed a machine-learning framework to accurately predict binding specificities and ligands of any MHC-II allele. This tool improves and expands predictions of CD4+ T cell epitopes and enables us to discover viral and bacterial epitopes following the aforementioned reverse-binding mode.

Keywords: MHC-II binding motifs; MHC-II ligand binding modes; antigen presentation; class II epitope predictions; computational immunology; immunopeptidomics; reverse binding mode.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cattle
  • Chickens / metabolism
  • Epitopes, T-Lymphocyte*
  • Histocompatibility Antigens Class II
  • Humans
  • Ligands
  • Machine Learning
  • Mice
  • Peptides*
  • Protein Binding


  • Epitopes, T-Lymphocyte
  • Ligands
  • Peptides
  • Histocompatibility Antigens Class II