Targeted Conversion of Pathogenic T Cells into Stabilized Regulatory T Cells: A Tailor-Made Approach for Suppressing Autoimmunity in Pemphigus

Antigen-specific immunotherapy holds promise for treating autoimmune diseases. Pemphigus is an autoimmune disorder mediated by anti-desmoglein 3 (Dsg3) autoantibodies. Here, we developed a therapeutic strategy that involves converting Dsg3-specific pathogenic CD4+ T cells into stable and functional inducible regulatory T cells (S/F-iTregs). This conversion is featured by inducing hypomethylation in the Foxp3 CNS2 region with Treg stability and function durable. Importantly, these S/F-iTregs autonomously remain highly immunoregulatory and numerically dominate over disease-unrelated S/F-iTregs by interacting endogenous autoantigens. Consequently, these S/F-iTregs selectively inhibit Dsg3-specific T and B cell proliferation without affecting responses to irrelevant antigens, therefore, mitigating disease phenotype and demonstrating potent immunoregulatory capacity in a pemphigus model. This approach also effectively generated functional iTregs from patients' blood cells, showcasing potential for personalized therapeutic applications. This study introduces a transformative approach by converting pathogenic T cells into disease-specific regulatory cells with identical antigen-specificity, offering a tailor-made strategy to curb individual autoimmunity.