Harnessing regulatory T (Treg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific Treg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific Treg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8+ T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-β, under which the autoantigenic peptides directed naïve CD4+ T cells to differentiate into Foxp3+ Treg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific T reg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific Treg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.
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