Secondary infections due to a marked immunosuppression have long been recognized as a major cause of the high morbidity and mortality rate associated with acute measles. The mechanisms underlying the inhibition of cell-mediated immunity are not clearly understood but dysfunctions of monocytes as antigen-presenting cells (APC) are implicated. In this report, we demonstrate that measles virus (MV) replicates weakly in the resting dendritic cells (DC) as in lipopolysaccharide-activated monocytes, but intensively in CD40-activated DC. The interaction of MV-infected DC with T cells not only induces syncytia formation where MV undergoes massive replication, but also leads to an impairment of DC and T cell function and cell death. CD40-activated DC decrease their capacity to produce interleukin (IL) 12, and T cells are unable to proliferate in response to MV-infected DC stimulation. A massive apoptosis of both DC and T cells is observed in the MV pulsed DC–T cell cocultures. This study suggests that DC represent a major target of MV. The enhanced MV replication during DC–T cell interaction, leading to an IL-12 production decrease and the deletion of DC and T cells, may be the essential mechanism of immunosuppression induced by MV.

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Measles virus (MV) infection induces a profound immunosuppression responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DCs) in the respiratory mucosa or in the secondary lymphoid organs. The purpose of this study was to investigate the consequences of DC infection by MV, particularly concerning their maturation and their ability to generate CD8+ T cell proliferation. We first show that MV-infected Langerhans cells or monocyte-derived DCs undergo a maturation process similarly to the one induced by TNF-α or LPS, respectively. CD40 ligand (CD40L) expressed on activated T cells is shown to induce terminal differentiation of DCs into mature effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression down-regulation. Moreover, the CD40L-induced cytokine pattern in DCs is modified by MV infection with inhibition of IL-12 and IL-1α/β and induction of IL-10 mRNAs synthesis. Using peripheral blood lymphocytes from CD40L-deficient patients, we demonstrate that MV infection of DCs prevents the CD40L-dependent CD8+ T cell proliferation. In such DC-PBL cocultures, inhibition of CD80 and CD86 expression on DCs was shown to require both MV replication and CD40 triggering. Finally, for the first time, MV was shown to inhibit tyrosine-phosphorylation level induced by CD40 activation in DCs. Our data demonstrate that MV replication modifies CD40 signaling in DCs, thus leading to impaired maturation. This phenomenon could play a pivotal role in MV-induced immunosuppression.

SummaryDuring antigen-induced immune responses, human B cells switch isotype from immunoglobulin M (IgM)-IgD to IgG1-4, IgA1-2, or IgE. In the human, no cytokines have yet been demonstrated to act as switch factors for IgG1, IgG2, and IgG3. In this paper, we report that in response to interleukin 10 (IL-10), anti-CD40 activated tonsillar surface IgD + (slgD +) B cells are induced to secrete large amounts of IgM, IgG1, and IgG3 but neither IgG2 nor IgG4. Cord blood purified B cells and lymphocytes from Hyper-IgM patients also produced IgG1 and IgG3 after culture with anti-CD40 and IL-10. In contrast, sIgD-isotype-committed B cells produce IgG1, IgG2, and IgG3 when activated through CD40 in the presence of IL-10. Thus, in addition to its growthpromoting and differentiating activities on human B calls, IL-10 may represent a switch factor for IgG1 and IgG3.

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

Mortality from measles virus (MV) infection is

The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-α- or IFN-γ-stimulated CD11c+ blood DCs and IFN-β-stimulated monocyte-derived DCs were recently reported to express functional TNF-related apoptosis-inducing ligand (TRAIL), suggesting that DCs may become cytotoxic effector cells of innate immunity upon appropriate stimulation. In this study, we investigate whether dsRNA and CD40 ligand (CD40L), that were characterized as potent inducers of DC maturation, could also stimulate or modulate DC cytotoxicity toward tumoral cells. We observed that dsRNA, but not CD40L, is a potent inducer of TRAIL expression in human monocyte-derived DCs. As revealed by cytotoxicity assays, DCs acquire the ability to kill tumoral cells via the TRAIL pathway when treated with dsRNA. More precisely, dsRNA is shown to induce IFN-β synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-α-treated DCs is potently inhibited after CD40L stimulation. Unexpectedly, CD40L-activated DCs still developed cytotoxicity toward tumoral cells. This latter appeared to be partly mediated by TNF-α induction and a yet unidentified pathway. Altogether, these results demonstrate that dsRNA and CD40L, that were originally characterized as maturation signals for DCs, also stimulate their cytotoxicity that is mediated through TRAIL-dependent or -independent mechanisms.

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