Conversion of pathogenic T cells into functionally stabilized T_reg cells for antigen-specific immunosuppression in...

Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti-desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4⁺ T cells were converted in vitro into functionally stable Foxp3⁺ regulatory T (T_reg) cells, designated stable and functional induced T_reg (S/F-iT_reg) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of T_reg cell-specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iT_reg cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iT_reg cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific T_reg cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.