The Roles of Type 2 Cytotoxic T Cells in Inflammation, Tissue Remodeling, and Prostaglandin (PG) D2 Production Are Attenuated by PGD2 Receptor 2 Antagonism

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD(2) and its receptor PGD(2) receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD(2)/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD(2) autocrine production. PGD(2) upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD(2) stimulated Tc2 cells to produce PGD(2) using the routine PGD(2) synthesis pathway, which also contributed to TCR-dependent PGD(2) production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD(2) but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD(2) production in Tc2 induced by PGD(2) and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.