Proinflammatory and immunoregulatory roles of eicosanoids in T cells

Abstract

Eicosanoids are inflammatory mediators primarily generated by hydrolysis of membrane phospholipids by phospholipase A2 to ω-3 and ω-6 C20 fatty acids that next are converted to leukotrienes (LTs), prostaglandins (PGs), prostacyclins (PCs), and thromboxanes (TXAs). The rate-limiting and tightly regulated lipoxygenases control synthesis of LTs while the equally well-controlled cyclooxygenases 1 and 2 generate prostanoids, including PGs, PCs, and TXAs. While many of the classical signs of inflammation such as redness, swelling, pain, and heat are caused by eicosanoid species with vasoactive, pyretic, and pain-inducing effects locally, some eicosanoids also regulate T cell functions. Here, we will review eicosanoid production in T cell subsets and the inflammatory and immunoregulatory functions of LTs, PGs, PCs, and TXAs in T cells.

Keywords: cAMP; cyclooxygenase 2; immunoregulation effect; inflammation; inflammation mediators; leukotrienes; prostaglandins; regulatory T cells.

Figure 1

General overview of synthesis pathways for eicosanoids. The biosynthetic pathway for the arachidonic acid-derived eicosanoids described in this article. The figure shows the structures of the relevant eicosanoids (black), and indicates the enzymes involved in their biosynthesis (blue), as well as the GPCRs through which these eicosanoids signal (red). PGF_2α can be synthesized through a number of different pathways.

Figure 2

Inhibitory pathway of PGE2 in effector T cells. PGE₂ mediates Treg inhibition of effector T cell function through a PKA-mediated pathway. (A) In response to continuous antigen exposure, for instance in cancer and HIV, adaptive regulatory T cells express COX-2 and produce PGE₂, which stimulates FOXP3 expression in these cells. The Treg-derived PGE₂ can signal through the EP2 and EP4 receptors on effector T cells to inhibit the function of these cells through the pathway shown in (B). Binding of PGE₂ to its receptors on effector T cells stimulates adenylyl cyclase activity, which increases intracellular cAMP levels and thus activates PKA. Aided by an Ezrin-EBP50-PAG scaffold, PKA phosphorylates Csk, which in turn phosphorylates Lck to inhibit its activity. Lck normally acts to promote TCR signaling; thus Lck inhibition through this PGE₂-initiated pathway inhibits TCR signaling in effector T cells.