A regulatory T cell-biased IL-2 mutein inhibits the development of allergen-specific Th2 cells and allergic asthma.

Abstract

Restoring durable allergen tolerance remains a challenge in the treatment of allergic asthma. Regulatory T cells (Tregs) represent attractive therapeutic targets since they can potently restrain allergen-specific type 2 effector T cell (Th2) responses. Agents that expand Tregs and enhance their function, such as interleukin-2 (IL-2)-based therapies, have been explored, but limited specificity has constrained their efficacy. IL-2 muteins have been engineered to preferentially target Tregs but have not been studied in the context of allergic inflammation. We explored the effects of the IL-2 mutein Fc.mut24 on allergen-induced type 2 airway inflammation. C57BL/6 mice were injected subcutaneously with Fc.mut24 in a house dust mite model of allergic airway inflammation, and clinical, cellular, and molecular biomarkers of the disease were assessed. In naïve mice, Fc.mut24 induced a rapid and transient expansion of activated Tregs in the lung. Fc.mut24 treatment prior to allergen sensitization abrogated the emergence of allergen-specific Th2 cells in the lung and prevented allergic airway inflammation and airway hyperreactivity. Further, Fc.mut24-pretreated mice failed to mount a Th2 recall response and did not develop lung inflammation upon allergen rechallenge during the memory phase, suggesting long-term protection. Maintenance of this protection required Tregs, as deletion of Tregs abolished the protective effect of Fc.mut24. In contrast, Fc.mut24 administered during the memory phase did not suppress the Th2 recall response and did not prevent allergic airway inflammation following rechallenge. Fc.mut24 therapy prevented allergic airway inflammation when delivered before Th2 cell priming but was insufficient to overcome established allergen-specific type 2 responses, defining a time-dependent window for effective Treg-directed intervention.