Cross-reactive self or foreign peptide-HLA complexes (pMHC)

Cross-reactive self or foreign peptide-HLA (pHLA) complexes are the fundamental units of recognition for the adaptive immune system, consisting of a short peptide fragment bound to a Human Leukocyte Antigen (HLA) molecule. These complexes are presented on the surface of almost all nucleated cells and are scanned by T-cell receptors (TCRs) to distinguish between self, foreign (viral/bacterial), or altered-self (cancer) antigens [Nature Reviews Immunology, 2019]. In modern immunotherapy, specific pHLA complexes are targeted by TCR-engineered T cells (TCR-T) and bispecific T-cell engagers to eliminate malignant cells with high precision [Journal of Hematology & Oncology, 2021]. However, the inherent flexibility of TCR recognition allows for cross-reactivity, where a single TCR may recognize multiple distinct pHLA complexes that share structural or chemical similarities [Frontiers in Immunology, 2020]. This phenomenon, often termed molecular mimicry, is a critical driver of autoimmune pathology and poses a significant safety hurdle in drug development, as seen in clinical trials where TCRs intended for tumor antigens cross-reacted with unrelated self-peptides in vital organs [Science Translational Medicine, 2013]. Consequently, these complexes are central to both the therapeutic efficacy of TCR-based biologics and the risk of severe adverse events [Blood, 2013].

Other names

Peptide-MHC complexespHLA complexesCross-reactive T-cell epitopesMolecular mimicry targetspMHC ligandsPeptide-Human Leukocyte Antigen complexes

Binding of engineered T-cell receptors (TCRs) or soluble TCR-fusion proteins to specific peptide-HLA complexes, leading to T-cell mediated lysis of target cells and cytokine release.