Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells

Background: Activation of the group 2 innate lymphoid cell (ILC2) population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH2), a receptor for prostaglandin D-2 (PGD(2)), is expressed by human ILC2s. However, the function of CRTH2 in these cells is unclear. Objectives: We sought to determine the role of PGD(2) and CRTH2 in human ILC2s and compare it with that of the established ILC2 activators IL-25 and IL-33. Methods: The effects of PGD2, IL-25, and IL-33 on the cell migration, cytokine production, gene regulation, and receptor expression of ILC2s were measured with chemotaxis, ELISA, Luminex, flow cytometry, quantitative RT-PCR, and QuantiGene assays. The effects of PGD(2) under physiologic conditions were evaluated by using the supernatant from activated mast cells. Results: PGD(2) binding to CRTH2 induced ILC2 migration and production of type 2 cytokines and many other cytokines. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA). The effects of PGD(2) on ILC2s could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist. Conclusions: PGD(2) is an important and potent activator of ILC2s through CRTH2 mediating strong proallergic inflammatory responses. Through IgE-mediated mast cell degranulation, these innate cells can also contribute to adaptive type 2 immunity; thus CRTH2 bridges the innate and adaptive pathways in human ILC2s.