In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response

Harnessing regulatory T (T_reg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific T_reg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific T_reg 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⁺ T_reg cells instead of into T effector cells in vivo. These antigen-specific T_reg 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 T_reg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.