Machine learning reveals limited contribution of trans-only encoded variants to the HLA-DQ immunopeptidome

• Published in: Communications biology 2023-04, Vol.6 (1), p.442-13, Article 442
• Main Authors: Nilsson, Jonas Birkelund, Kaabinejadian, Saghar, Yari, Hooman, Peters, Bjoern, Barra, Carolina, Gragert, Loren, Hildebrand, William, Nielsen, Morten
• Format: Article
• Language: English
• Subjects: 631/114/1305; 631/250/21/324/1508; 82/1; 82/16; 82/58; Antigen presentation; Autoimmune Diseases; Biology; Biomedical and Life Sciences; Chromosomes; Data mining; Histocompatibility antigen HLA; HLA Antigens; HLA-DQ Antigens - chemistry; HLA-DQ Antigens - genetics; Humans; Immune response (cell-mediated); Life Sciences; Lymphocytes T; Machine Learning; Mass spectroscopy; Molecular modelling; T-Lymphocytes
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04749-7

Human leukocyte antigen (HLA) class II antigen presentation is key for controlling and triggering T cell immune responses. HLA-DQ molecules, which are believed to play a major role in autoimmune diseases, are heterodimers that can be formed as both cis and trans variants depending on whether the α- and β-chains are encoded on the same (cis) or opposite (trans) chromosomes. So far, limited progress has been made for predicting HLA-DQ antigen presentation. In addition, the contribution of trans-only variants (i.e. variants not observed in the population as cis) in shaping the HLA-DQ immunopeptidome remains largely unresolved. Here, we seek to address these issues by integrating state-of-the-art immunoinformatics data mining models with large volumes of high-quality HLA-DQ specific mass spectrometry immunopeptidomics data. The analysis demonstrates highly improved predictive power and molecular coverage for models trained including these novel HLA-DQ data. More importantly, investigating the role of trans-only HLA-DQ variants reveals a limited to no contribution to the overall HLA-DQ immunopeptidome. In conclusion, this study furthers our understanding of HLA-DQ specificities and casts light on the relative role of cis versus trans-only HLA-DQ variants in the HLA class II antigen presentation space. The developed method, NetMHCIIpan-4.2, is available at https://services.healthtech.dtu.dk/services/NetMHCIIpan-4.2 . The analysis integrating immunoinformatics data mining models with large volumes of high-quality HLA-DQ specific immunopeptidomics data reveals trans-only HLA-DQ variants have a limited to no contribution to the overall HLA-DQ immunopeptidome.