Abstract Introduction CD4+ regulatory T (Treg) cells are essential for immune tolerance. Peripherally induced Tregs (pTregs) complement thymic Tregs by broadening Treg reactivity in response to a changing antigenic landscape. Although both TGF-β and Interleukin-2 (IL-2) synergistically promote functional pTreg development in vitro, their combined roles in inducing pTreg generation in vivo are yet to be exploited for tolerizing immunotherapy. Methods We designed an IL-2-TGF-β “surrogate” co-agonist by creating a single-chain fusion protein between IL-2 and a low-affinity TGF-β mimic agonist derived from a Helminth parasite. This IL-2-TGF-β surrogate functions as an AND-gated co-agonist and enabled simultaneous cis-activation of both IL-2-STAT5 and TGF-β-SMAD2/3 signaling specifically in IL-2 receptor-expressing T cells. Results The IL-2-TGF-β surrogate agonist robustly induced antigen-specific, functional, and stable pTregs in vivo within peripheral lymphoid organs in OVA- or MOG35-55-immunized mice. The induced pTregs display an effector-like, actively expanding state with high Rorγt expression, enabling efficient migration and suppression of intestinal inflammation. Conclusion Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, portending a strategy for the induction of antigen-specific pTregs in vivo to establish immune tolerance in inflammatory, allergic, and autoimmune diseases. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Sun et al. (Tue,) studied this question.