Prostaglandin D2 differentially regulates functions of human NK cell subsets through distinct receptors

Human peripheral Natural Killer (NK) cells are phenotypically identified as CD161+CD3− cells that can be divided into three subsets based on the expression of CD56: CD56−, CD56low and CD56high cells. CD56low and CD56high NK cells together constitute the majority of human peripheral NK cells. These CD56+ cells produce a type-1 cytokine, IFN-γ, and play critical roles in the immune defense against tumors and virus infections. On the other hand, CD56− cells constitute a minor subpopulation of NK cells, some of which are capable of producing type-2 cytokines (IL-13 and IL-4). Type-2 cytokine producing NK cells have been suggested to participate in allergic responses. In the current work, we have demonstrated that CD56+ NK cells express a prostaglandin D2 (PGD2) receptor, D prostanoid receptor (DP). PGD2 signaling through DP suppresses cytotoxicity, cytokine production, chemotaxis and Ca2+ mobilization of CD56+ NK cells. Alternatively, a significant proportion of CD56− NK cells express another PGD2 receptor, chemoattractant receptor-like molecule on Th-2 cells (CRTH2). We have shown that the majority of type-2 cytokine producing NK cells in circulation are CRTH2+CD56− NK cells and these cells can accumulate in the allergic airways of asthmatic subjects upon allergen challenge. Our findings suggest that this chemotactic migration of CRTH2+CD56− NK cells is induced by PGD2 signaling through CRTH2. Together, these results identify novel mechanisms by which PGD2 can differentially regulate activities of NK cell subsets. The data also significantly improve the characterization of type-2 NK cells and further suggest their possible involvement in allergic diseases