Activated Macrophages Infected with Legionella Inhibit T Cells by Means of MyD88-Dependent Production of Prostaglandins

Abstract

To understand how macrophages (Mφ) activated with IFN-γ modulate the adaptive immune response to intracellular pathogens, the interaction of IFN-γ-treated bone marrow-derived murine Mφ (BMφ) with Legionella pneumophila was investigated. Although Legionella was able to evade phagosome lysosome fusion initially, and was capable of de novo protein synthesis within IFN-γ-treated BMφ, intracellular growth of Legionella was restricted. It was determined that activated BMφ infected with Legionella suppressed IFN-γ production by Ag-specific CD4 and CD8 T cells. A factor sufficient for suppression of T cell responses was present in culture supernatants isolated from activated BMφ following Legionella infection. Signaling pathways requiring MyD88 and TLR2 were important for production of a factor produced by IFN-γ-treated BMφ that interfered with effector T cell functions. Cyclooxygenase-2-dependent production of PGs by IFN-γ-treated BMφ infected with Legionella was required for inhibition of effector T cell responses. From these data we conclude that activated Mφ can down-modulate Ag-specific T cell responses after they encounter bacterial pathogens through production of PGs, which may be important in preventing unnecessary immune-mediated damage to host tissues.

Toll-Like Receptor 9 Regulates the Lung Macrophage Phenotype and Host Immunity in Murine Pneumonia Caused byLegionella pneumophila

“…Several TLRs are important for host responses against Legionella infection. Specifically, TLR2 is required for murine macrophage cytokine and prostaglandin responses to purified L. pneumophila lipid A and intact L. pneumophila (33). It has been shown that the L. pneumophila flagellin protein activated TLR5, and polymorphisms of TLR5 in humans have been linked to enhanced susceptibility to Legionnaires' disease (17,18).…”

MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

“…Thus, in vitro, wild-type Lpn replicate efficiently within (50-to 100-fold increase in Lpn CFU in 24 h) and eventually lyse macrophages (48). It has been shown in vitro that if macrophages are activated by pretreatment with exogenous IFN-␥, Lpn fails to replicate in these cells (47,49,50). The action of IFN-␥ arms the macrophages to avoid establishment of the replication-competent vacuole, such that the Lpn-containing phagosomes mature along the default pathway into phagolysosomes, thereby blocking Lpn replication and eventually killing the pathogen.…”

Down-Modulation of TCR Expression by Salmonella enterica serovar Typhimurium

“…To block PGE 2 production, the T cells were cultured in the presence of 1 M indomethacin (an inhibitor of both cyclooxygenase-1 and -2; Cayman Chemicals) as previously described (29,30). Where noted, a Transwell with 0.4-m pore polycarbonate membrane insert (Corning Life Sciences; Costar) was used to separate S. Typhimurium from the T cells, and a polyethersulfone membrane with 0.2-m pore (Nalgene) was used to obtain T cell culture supernatant.…”