Host self-peptide–Human Leukocyte Antigen complex (self-peptide–HLA)

Host self-peptide–Human Leukocyte Antigen (HLA) complexes are molecular structures consisting of an endogenous peptide fragment bound to an HLA molecule on the cell surface. These complexes become significant in clinical medicine when they are cross-recognized by T-cell receptors (TCRs) that were originally specific for viral antigens, such as those from Epstein-Barr Virus (EBV), or tumor-associated oncogenes. This cross-reactivity, often termed molecular mimicry, is a primary driver of autoimmune pathology; for example, EBV-specific TCRs have been shown to recognize GlialCAM peptides in the central nervous system, contributing to the development of Multiple Sclerosis (Lanz et al., 2022, Nature). In the field of cancer immunotherapy, these complexes represent a major safety hurdle for TCR-engineered T-cell therapies. A notable instance involved TCRs targeting the MAGE-A3 oncogene that cross-reacted with a self-peptide from the muscle protein titin, resulting in severe off-target cardiotoxicity (Linette et al., 2013, Blood). Consequently, these complexes are not only targets of pathological immune responses but also critical anti-targets that must be screened during the development of adoptive cell therapies to prevent adverse events (Cameron et al., 2013, Science Translational Medicine).

Other names

Cross-reactive self-antigenMolecular mimicry targetOff-target peptide-HLA complexpMHC complexSelf-pMHC

T-cell receptor (TCR) binding to the peptide-HLA complex triggers T-cell activation, cytokine release, and cytotoxic lysis of the target cell.