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.