Machine learning reveals limited contribution of trans-only encoded variants to the HLA-DQ immunopeptidome
Jonas Birkelund Nilsson, Saghar Kaabinejadian, Hooman Yari, Bjoern Peters, Carolina Barra, Loren Gragert, William H. Hildebrand, Morten Nielsen
Abstract
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 .