Chen, Wentao, Luo, Jian, Ye , Yuan, Hoyle, Ryan, Liu, Wei, Borst, Rowie, Kazani, Shamsah, Shikatani, Eric, Erpenbeck, Veit, Pavord, Ian, Klenerman, Paul, Sandham, David and xue, luzheng (2021) Prostaglandin D2 drives tissue remodelling functions and prostaglandin D2 autocrine production in type 2 cytotoxic T cells. The journal of immunology, 206. pp. 2714-2724. ISSN 1550-6606

Abstract

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. Prostaglandin D2 (PGD2) and its receptor prostaglandin D2 receptor 2 (DP2) play important roles in Tc2 cell activation including migration, cytokine production and survival. In this study, we revealed novel functions of the PGD2/DP2 axis in Tc2 cells to induce pro-tissue remodelling effects and immunoglobulin E (IgE)-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue remodelling genes in Tc2 cells, which enhanced fibroblast proliferation and protein production required for tissue repairing and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to T cell receptor-dependent PGD2 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 PGD2, but also attenuated pro-tissue remodelling effects and autocrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding on the role of Tc2 cells in the pathogenesis of asthma.

Item Type:	Article
Date Deposited:	22 Jun 2021 00:45
Last Modified:	22 Jun 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43307