TCR recognition of peptide–HLA class II complexes in autoimmunity: Structural insights for therapeutic targeting

T-cell clones escape central and peripheral tolerance, yet these mechanistic insights have so far only partially been translated into therapeutic design. In this review, we first summarize key features of self-reactive versus pathogen-specific pHLA II recognition in autoimmune diseases. We compiled all 38 currently resolved human ternary TCR-pHLA II complexes that are directly linked to autoimmune disease, 19 of these involve celiac diseases, whereas only a handful represent other autoimmune indications. Even with the relatively sparse structural dataset for this axis, current knowledge has helped shape emerging therapeutic strategies such as pHLA II-based nanomedicines, engineered regulatory T cells and TCR-like antibodies. We further discuss how artificial intelligence and machine-learning frameworks could integrate each patient's HLA class II genotype, peptide-presentation profile and autoreactive T-cell repertoire to design genuinely personalised, HLA II-stratified therapies, outlining this as a key future direction for the field.