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-beta, under which the autoantigenic peptides directed naive CD4(+) T cells to differentiate into Foxp3(+) T-reg 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 T-reg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.