Antigen-specific Treg engineering: from structural receptor-antigen recognition to next-generation tolerance therapies

Antigen-specific immune tolerance is widely regarded as the ideal outcome for autoimmune therapy: silencing pathogenic immune responses without global immunosuppression. Regulatory T cells (Tregs) are central to this goal, and advances in structural and molecular immunology have clarified how engineered receptors recognize disease-relevant antigens with high specificity. Depending on the antigen and disease context, this recognition can be built through several complementary platforms: T cell receptors (TCRs) engineered against peptide-MHC (pMHC) complexes, chimeric antigen receptors (CARs) directed at surface antigens, chimeric autoantibody receptors (CAARs) that exploit autoreactive B cell receptors as a targeting handle, or antibody-derived binding domains grafted onto Treg signaling scaffolds. Transducing any of these constructs into Tregs redirects suppression to the exact tissue and antigen driving disease. Despite promising preclinical results in conditions such as multiple sclerosis, ANCA-associated vasculitis, and Sjögren's disease, translating these structural and engineering advances into validated, clinic-ready therapies remains an open challenge.This Research Topic aims to bridge structural and molecular understanding of antigen recognition with the engineering, validation, and translation of antigen-specific Treg therapies — across TCR-, CAR-, CAAR-, and antibody-based platforms. Rather than treating immune tolerance as an abstract mechanism, we want contributions anchored in specific, disease-relevant antigens, so that structural and cellular engineering insights translate directly into testable therapeutic strategies. We welcome studies that resolve how receptor docking geometry, binding affinity, and antigen stability determine Treg specificity and function; that engineer and functionally validate antigen-specific TCR-, CAR-, CAAR-, or antibody-based Treg constructs; and that test these therapies in relevant preclinical or patient-derived systems. The goal is a collection that moves the field from structural/molecular characterization toward therapies with a clear path to clinical translation, giving researchers across structural biology, immunology, protein engineering, and translational medicine a shared reference point for antigen-specific Treg engineering.We invite submissions spanning: Structural and Computational Design (crystallography, AlphaFold modeling, and molecular dynamics of TCR-pMHC, CAR-antigen, CAAR-autoantibody, or antibody-antigen interactions informing receptor selection for Treg redirection); In Vitro Validation (TCR-, CAR-, CAAR-, or antibody-based Treg construct generation, transduction/transfection efficiency, flow cytometric phenotyping, and functional suppression assays against defined antigens); In Vivo Preclinical Models (efficacy, trafficking, and persistence of engineered Tregs in humanized or disease-relevant models such as EAE, passive-transfer AAV, NOD, and CIA); and Patient-Derived Validation (studies using patient PBMCs, biopsies, or ex vivo TCR/BCR repertoires to identify candidate antigens or biomarkers of restored tolerance). We welcome Original Research, Review, Mini-Review, Methods, Perspective, and Hypothesis & Theory articles. Topic editors: Yi Tian Ting, Petr O Ilyinskii, Xiaoyu Jia Source: https://www.frontiersin.org/research-topics/86299/antigen-specific-treg-engineering-from-structural-receptor-antigen-recognition-to-next-generation-tolerance-therapies