IL-33 and IL-4 Synergize to Dysregulate TREG Cell Function and Promote Type 2 Responses in RSV-induced Asthma

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants and is associated with asthma development. While the way neonatal infections induce long-term immune alterations remain ill-defined, there is evidence regulatory T (T_REG) cells fail in preventing pulmonary T_H2 responses. Since IL-33 is an alarmin involved in the exacerbation of T_H2 responses, we hypothesized that neonatal RSV infections impair the long-term suppressive function of IL-33-responding (ST2⁺) T_REG while contributing to T_H2-induced pathology.

Using an RSV A2 murine model of infection, we uncovered that, contrary to conventional T_H2 cells, ST2⁺ T_REG fail to accumulate in the lungs at the time of neonate infection but expand robustly and express GATA3 and IL-13 upon re-infection in adult BALB/c mice. Through a Foxp3-specific ST2 conditional knock-out mouse sensitized to house dust mite, we observed that ST2⁺ T_REG are required for controlling exacerbated T_H2 cell responses in mice naturally resistant to type 2 immunity. Indeed, while IL-33 potentiated the expression of the IL4Rα, IL-4, in turn, drove the production of IL-10 by T_REG. However, increasing amounts of IL-4 also contributed to dysregulate the suppressive capacity of T_REG cells in vitro and drive a T_H2-like conversion of T_REG (IL-13⁺, IL-5⁺, GATA3⁺) in a STAT6-dependent manner, suggesting that tight control of IL-4 signaling is required for ST2⁺ T_REG to suppress T cells.

These initial studies suggest RSV induced IL-33 sensitizes local T_REG to T_H2 produced IL-4 that ultimately dysregulate their suppressive capacity. This work provides a novel target for the development of asthma therapies.