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.