Human leukocyte antigen A*02:01-restricted self-peptides (HLA-A*02:01 self-peptides)

Human leukocyte antigen A*02:01-restricted self-peptides are a diverse group of endogenous protein fragments, typically 8 to 11 amino acids in length, that are presented on the cell surface by the HLA-A*02:01 molecule, a common MHC Class I allele. These peptides are derived from the degradation of normal cellular proteins and play a fundamental role in the immune system by maintaining self-tolerance and educating CD8+ T cells in the thymus (PMID: 29343439). In the context of modern immunotherapy, such as T-cell receptor (TCR)-engineered T cells or bispecific T-cell engagers, these self-peptides are primarily viewed as critical safety hurdles rather than intended therapeutic targets. If a therapeutic agent designed to target a tumor-specific antigen cross-reacts with any of these widely expressed self-peptides, it can lead to severe off-target, off-tumor toxicity. A notable example occurred in clinical trials where a TCR targeting MAGE-A3 cross-reacted with a self-peptide from the muscle protein Titin, resulting in fatal cardiotoxicity (PMID: 23943601). Consequently, the comprehensive mapping of the HLA-A*02:01 immunopeptidome is essential for ensuring the specificity and safety of MHC-restricted biologics.

Other names

HLA-A2 restricted self-antigensEndogenous HLA-A*02:01 ligandsNormal tissue immunopeptidomeMHC class I-restricted self-peptidesHLA-A*02:01-presented endogenous peptides

Recognition by T-cell receptors (TCRs) or TCR-mimetic antibodies, leading to T-cell activation, cytokine release, or immune-mediated cell lysis.