Bulk RNA-seq of ILC2, Tconv, Th2, Treg Gata3hi and Treg Gatalo from the lungs of IL-33 treated mice

Regulatory T cells (Tregs) are essential for limiting adaptive immunity, and restrain type-2 inflammation in allergic disease. As Tregs function locally, the mechanisms that coordinate their suppressive role in the inflamed niche are of great interest. Here we show that group 2 innate lymphoid cells (ILC2) are critical mediators of IL-33-driven Treg expansion in allergic inflammation. ILC2-derived OX40L promotes the local expansion of Gata3high Tregs, which possess distinct transcriptional and functional programmes that enforce co-localisation with ILC2 in the inflamed airways. Using OX40 Treg-conditional mutant mice, we show that Gata3high Tregs are important for restraining adaptive type-2 immunity. Mechanistically, Gata3high Tregs modulate OX40L bioavailability on ILC2, which controls effector memory Th2 cell formation. As such, ILC2 can simultaneously engage both the effector and regulatory arms of adaptive type-2 immunity via the OX40L-OX40 signalling axis. More specifically, ILC2-Treg interactions serve as a critical feedback mechanism to control adaptive type-2 immunity.