Selective Immune Silencing by Targeted TGF-β Agonists

Depletion of pathogenic T and B cells is a pillar of first-line therapies for inflammatory, autoimmune, and transplantation-related immunological diseases. However, concerns about adverse events, safety in immunocompromised patients, and disease relapse from incomplete depletion, limit clinical utility. Here, we exploit the immunosuppressive properties of Transforming growth factor beta (TGF-β), through selective "silencing" of T and B cells by a targeted TGF-β mimic agonist derived from Helminths. CD4 and CD8 T cell-targeted TGF-β agonists effectively silence antigen-stimulated T cell activation and expansion in mice and human spleen organoids. A mouse CD4 T cell-targeted TGF-β agonist silences antigen-specific antibody responses by reprogramming pro-inflammatory Th1 and T follicular helper cells into quiescent or regulatory T cell phenotypes <i>in vivo</i>. A human CD19 B cell-targeted TGF-β agonist silences antibody responses by disrupting differentiation of germinal center B cells into antibody-secreting cells in human spleen organoids. Cell-type-specific targeted TGF-β agonists ameliorate disease activity in multiple mouse models with minimal off-target effects <i>in vivo</i>. Thus, cell-selective TGF-β agonism is a versatile therapeutic strategy for precise silencing of immune functions.