Selective Immune Silencing by Targeted TGF-β Mimics

Abstract Depletion of pathogenic T and B cells is a pillar of therapies for autoimmune, inflammatory, and transplantation-related immunological diseases. However, adverse events, safety concerns in immunocompromised patients, and disease relapse limit clinical utility. Here, we exploit the immunosuppressive properties of a transforming growth factor beta (TGF-β) mimic repurposed from helminths for cell type–specific therapeutic “silencing”, as a new approach to complement existing therapies. Mouse CD4⁺ and CD8⁺ T cell–targeted TGF-β agonists selectively and potently silence antigen-specific T cell responses in OVA-immunized mice by suppressing pro-inflammatory effector, cytotoxic, and T follicular helper programs, while skewing cells toward a quiescent state biased toward regulatory and type 17 T cell phenotypes. Similarly, human CD4⁺ and CD8⁺ T cell–targeted TGF-β agonists precisely and effectively suppress live-attenuated influenza vaccine (LAIV)-induced T cell activation and expansion in human spleen organoids. Correspondingly, CD4⁺ T cell-targeted TGF-β agonist effectively ameliorated disease activity and promoted disease remission in CD4⁺ T cell-driven models of autoimmune neuroinflammation and allergic airway inflammation, demonstrating efficacy in both prophylactic and established inflammatory settings. Moreover, both CD4⁺ and CD8⁺ T cell-targeted TGF-β agonists ameliorated disease activity in graft-versus-host disease. Additionally, a human CD19⁺ B cell–targeted TGF-β agonist robustly inhibits germinal center B cell-to-plasmablast maturation and antibody responses in LAIV-stimulated human spleen organoids. These early-stage results suggest that cell-selective TGF-β agonism merits further investigation as a versatile therapeutic approach for the precise silencing of pathogenic adaptive immune responses.