The PGD2/DP2 axis promotes pro-inflammatory responses but attenuates an antigen-presenting role of human basophils.

Basophils are distinct blood leucocytes that express immunoglobulin E (IgE) receptor FcεR1 and can be activated by IgE. Their roles in asthma, particularly IgE-independent effects, remain incompletely understood. Human basophils highly express the prostaglandin D2 (PGD2) receptor 2 (DP2; also known as chemoattractant receptor homologous molecule expressed on Th2 cells, CRTH2). Here, we explore the PGD2/DP2 axis as an alternative pathway for basophil activation. Basophils are enriched in patients with severe eosinophilic asthma, correlating with eosinophil counts but not IgE levels. PGD2/DP2 stimulation promotes basophil recruitment, activation, and the production of histamine, leukotrienes, and type 2 cytokines. RNA sequencing and further in vitro experiments reveal that, although PGD2 and IgE share some signalling pathways and functions, they induce distinct gene transcriptional signatures. Interestingly, PGD2 downregulates major histocompatibility complex class I-related gene protein (MR1) and attenuates basophil antigen-presentation to mucosal-associated invariant T (MAIT) cells, leading to reduced IFN-γ production. These findings highlight the PGD2/DP2/basophil axis as a contributor to asthma, particularly in IgE-low conditions, and suggest it as a potential therapeutic target for related diseases.