TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

Abstract

Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor(s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E 2 (PGE 2 ) and showed that both APC-derived supernatants and PGE 2 prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE 2 receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE 2 . Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE 2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival. Cell Death and Differentiation (2008) 15, 1901-1909 doi:10.1038/cdd.2008 ; published online 26 September 2008Proper activation of T cells is imperative to achieve an efficient immunity against pathogens and tumors and, at the same time, to avoid undesirable collateral effects, such as the appearance of autoimmune diseases. Secondary lymphoid organs provide a particular microenvironment specialized in assembling all the cohorts necessary to perform such a remarkable task. 1 In the presence of antigens, antigenpresenting cells (APCs) and their soluble products, including a variety of cytokines, lipid mediators and chemokines, T cells are activated through the engagement of their T-cell receptors (TCR) and co-stimulatory molecules. As a result, T cells can proliferate, differentiate to effector or memory cells, or eventually die.Deletion of autoreactive T cells is one of the key mechanisms involved in the process of peripheral tolerance that helps to prevent the appearance of autoimmune diseases. 2 Similarly, elimination of chronically stimulated T cells that can potentially be harmful to the host by the means of the production of abnormal levels of inflammatory cytokines is another feature of an efficient immune system. Finally, death of effector T cells at the end of an immune response is a very important homeostatic mechanism designed to shrink an enlarged, no longer necessary cell population that can compete for growth and survival factors with newly activated antigen-specific T-cell clones. In a...

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