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

Autoimmune diseases encompass a broad spectrum of disorders in which self-reactive T and B cells breach immune tolerance and drive chronic tissue inflammation. Although broad immunosuppressants and cytokine-targeted biologic therapies have improved disease management, many patients still fail to achievement drug-free remission and often relapsed once medication is withdrawn. Human Leukocyte Antigen (HLA) class II genes, the most polymorphic in the human genome, are major determinants of autoimmune disease risk. Polymorphism in HLA class II, concentrated in the peptide-binding groove, shapes the repertoire of self-peptides that can be presented to the immune system. This peptide-HLA complexes (pHLA) therefore influences which autoreactive CD4⁺ 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.