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

Shimpei Kasagi, Pin Zhang, Li Che, Brittany Abbatiello, Takashi Maruyama, Hiroko Nakatsukasa,Peter Zanvit, Wenwen Jin, Joanne E. Konkel, WanJun Chen

Science Translational Medicine 2014 6:241ra78

Speaker: Chi-Ting Hsieh (謝其庭)                                   Time: 14:00~15:00, Sep.17, 2014

Commentator: Dr. Chrong-Reen Wang (王崇任老師)         Place: Room 601

Abstract:

       Propagation of regulatory T (T_reg) cells that maintain immune tolerance to self-antigens is a reasonable way to treat autoimmune diseases. Previous studies show that antibody-induced cell apoptosis can promote immune tolerance, which depends on the macrophage engulfing apoptotic cells and producing transforming growth factor β (TGF-β), a cytokine driving T_reg cell differentiation. However, systemic circulation of non-specific T_reg cells raises a risk of general immunosuppression and undesired susceptibility to infection. In this study, the authors tested how to induce therapeutic T_reg cells specific to target autoantigens in two autoimmune mouse models, experimental autoimmune encephalomyelitis and type I diabetes. To simultaneously destroy existing autoimmune environment and generate tolerogenic apoptotic cells in vivo, they performed systemic γ-irradiation plus macrophage restoration or specifically killed B cells and CD8⁺ T cells by antibody-mediated depletion. Subsequently, to induce antigen-specific T_reg cells in vivo, they repeatedly injected target autoantigens. These approaches not only significantly induced autoantigen-specific T_reg cells from naïve CD4⁺ T cells, but also successfully suppressed established autoimmune diseases in mice without impairing the immune responses to Mycobacterium tuberculosis. Factors essential for the therapeutic effects included CD25⁺ (T_reg) cells, macrophages, TGF-β and autoantigens. In conclusion, the combination of cell apoptosis induction and subsequentautoantigen administration can “reprogram” the in vivo environment from inflammation/autoimmune to immune tolerance, and can be potentially applied to clinical treatment.

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