The widely expressed transmembrane molecule CD46 is the complement regulatory receptor for C3b as well as the receptor for several pathogens. Beside its binding functions, CD46 is also able to transduce signals. We showed that CD46 aggregation on human T cells induces p120CBL and linker for activation of T cells (LAT) phosphorylation. These two proteins are adaptor proteins known to regulate TCR signaling. p120CBL is a complex adaptor protein involved in negatively regulating signaling events, whereas LAT is a transmembrane adaptor protein found in glycolipid-enriched microdomains essential for T cell activation. Therefore, we investigated if a CD46/TCR costimulation would affect T cell activation. Indeed, CD46/CD3 costimulation strongly promotes T cell proliferation. Therefore, we propose that CD46 acts as a potent costimulatory molecule for human T cells.
Measles virus infection induces a profound immunosuppression that can lead to serious secondary infections. Here we demonstrate that measles virus induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression in human monocyte-derived dendritic cells. Moreover, measles virusinfected dendritic cells are shown to be cytotoxic via the TRAIL pathway.Secondary infections due to a marked immunosuppression have long been recognized as a major cause of the high morbidity and mortality rates associated with measles virus (MV) infection. The mechanisms underlying the inhibition of cellmediated immunity following MV infection are not clearly understood, but dysfunction of MV-infected monocytes (7, 9, 10) and dendritic cells (DCs) as antigen-presenting cells (3, 5, 12) has been described. In previous work, we demonstrated induction of T-cell apoptosis by MV-infected DCs (3). To account for this killer activity of MV-infected DCs, we investigated tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression in human monocyte-derived DCs after MV infection. TRAIL is a type II transmembrane protein that was initially identified based on the homology of its extracellular domain with those of TNF family members (15). TRAIL does not seem to be cytotoxic toward normal cells but induces apoptosis of a wide variety of transformed cell lines (6,14). Moreover, T cells from human immunodeficiency virus (HIV) type 1-infected patients, which were previously shown to exhibit increased Fas sensitivity, are even more susceptible to TRAIL-induced cell death (6,8). These data suggest that TRAIL may participate in apoptosis of lymphoid cells and that it may be involved in dysregulated apoptosis following infection by immunosuppressive viruses such as HIV type 1. Here we demonstrate for the first time that functional TRAIL is produced by MV-infected DCs and mediates their cytotoxic activity.DCs were obtained from purified peripheral blood monocytes cultured for 6 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 as previously described (3). DCs were infected with 1 PFU of Vero cell-derived MV (Edmonston strain) per cell for 3 h at 37°C, then washed and placed in culture. Cells were harvested 4, 8, 12, and 24 h after infection, and total RNA was extracted. TRAIL mRNA expression was quantified by an RNase protection assay (Riboquant hApo3) in accordance with the manufacturer's (PharMingen, San Diego, Calif.) specifications. As shown in Fig. 1A
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