Self-peptide–Human Leukocyte Antigen complex (Self-pHLA)

Self-peptide–Human Leukocyte Antigen (self-pHLA) complexes are molecular assemblies consisting of a self-derived peptide fragment bound to an HLA molecule on the cell surface. While the primary role of these complexes is to maintain self-tolerance, certain self-peptides possess sequence or structural similarity to foreign viral epitopes, tumor-associated antigens (TAAs), or minor histocompatibility antigens (mHAgs) (Hellman et al., 2014). This similarity can lead to molecular mimicry, where therapeutic T cells or antibodies intended for a pathogen or tumor inadvertently recognize and attack healthy tissues (Riley et al., 2019). In the context of modern immunotherapy, such as TCR-engineered T-cell therapy, these complexes represent a critical safety liability rather than a therapeutic target. Identifying and screening against these cross-reactive self-epitopes is essential to prevent lethal off-target toxicities, as seen in historical clinical trials where T cells targeting MAGE-A3 cross-reacted with Titin in cardiac tissue (Linette et al., 2013; Cameron et al., 2013).

Other names

Molecular mimicsCross-reactive self-epitopesOff-target pHLA complexesMimicry epitopesSelf-peptide-MHC complexes

Off-target T-cell activation via molecular mimicry or structural cross-reactivity with intended therapeutic epitopes.