Cross-talk Between ILC2 and Gata3 High T Regs Locally Constrains Adaptive Type 2 Immunity

Regulatory T cells (T regs ) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident T regs and group 2 innate lymphoid cells (ILC2s); however, how T regs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of T reg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and T regs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3 high T regs , which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-T reg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3 high T regs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-T reg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.