Conversion of pathogenic T cells into functionally stabilized T <sub>reg</sub> cells for antigen-specific immunosuppression in pemphigus vulgaris
Miho Mukai, Hayato Takahashi, Yoko Kubo, Yasuhiko Asahina, Hisato Iriki, Hisashi Nomura, Aki Kamata, Hiromi Ito, Yutaka Kurebayashi, Jun Yamagami, Norihisa Mikami, Shimon Sakaguchi, Masayuki Amagai
Abstract
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.