Efficient T‐cell priming and activation requires signaling through prostaglandin E2 (EP) receptors

Abstract

Understanding the regulation of T-cell responses during inflammation and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E2 (PGE2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE2 during T-cell receptor stimulation. In addition, we show that autocrine PGE2 signaling through EP receptors is essential for optimal CD4(+) T-cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE2 was found to provide additive co-stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell-dendritic cell (DC) interactions and Th-cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen-induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T-cell activation, accompanied by a decline in activated and interferon-γ-producing CD4(+) Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE2, which in turn provide additive co-stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T-cell activation and development of T cell-mediated inflammatory responses. This may have implications in various pathophysiological settings.

Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression

“…Prostaglandin E2 signaling through EP2 has been shown to promote the differentiation and pro-inflammatory functions of human and murine T H 17 and T H 1 cells (Boniface et al, 2009). Furthermore, blocking EP2 receptors in T cells has been shown to be effective in preventing the development of arthritis in mouse models (Sreeramkumar et al, 2016). Given the increased propensity of women to develop autoimmune arthritis and the pathogenic role of T H 17 cells in driving its disease pathogenesis, we speculate that the increased expression of PTGER2 transcripts in females may play a role in amplifying pathogenic T H 17 responses that lead to the development of arthritis.…”

Microsomal Prostaglandin E Synthase-1 Facilitates an Intercellular Interaction between CD4+ T Cells through IL-1β Autocrine Function in Experimental Autoimmune Encephalomyelitis

“…Because all four EP receptors were shown to be expressed in neurons and induced in VECs under conditions of hypoxic–ischemic encephalopathy [ 38 ], EP receptors are known to be inducible in pathological conditions. In previous studies, T cells were regulated by PGE 2 , and this effect was mediated by EP2 or EP4 [ 39 , 40 , 41 ]. Moreover, IL-1β upregulated EP2 and EP4 in primary cultured hippocampal neurons [ 42 ].…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…Apart from the direct suppression of immune cell activities, EP2 signaling can promote the development of regulatory T cells, which are efficient inhibitors of the immune system and can suppress the activity of numerous immune cells, including dcs (67). dcs have a key role in the initiation of the tumor-specific immune response (52).…”