Prostaglandin D₂ suppresses human NK cell function via signaling through D prostanoid receptor

NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD ₂. PGD₂ is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD₂ binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD₂ inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD₂ signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD₂ binding to DP suppresses Ca²⁺ mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD ₂ functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response.