Perpetual complexity: predicting human CD8⁺ T-cell responses to pathogenic peptides

The accurate prediction of human CD8⁺ T-cell epitopes has great potential clinical and translational implications in the context of infection, cancer and autoimmunity. Prediction algorithms have traditionally focused on calculated peptide affinity for the binding groove of MHC-I. However, over the years it has become increasingly clear that the ultimate T-cell recognition of MHC-I-bound peptides is governed by many contributing factors within the complex antigen presentation pathway. Recent advances in next-generation sequencing and immunnopeptidomics have increased the precision of HLA-I sub-allele classification, and have led to the discovery of peptide processing events and individual allele-specific binding preferences. Here, we review some of the discoveries that initiated the development of peptide prediction algorithms, and outline some of the current available online tools for CD8⁺ T-cell epitope prediction.