[Measles virus and immunosuppression].
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Humans↗
Biomedical subjects
C Servet-Delprat
Publications and source records attributed to C Servet-Delprat.
Measles virus and dendritic cell functions: how specific response cohabits with immunosuppression.
Measles virus (MV) infection induces both an efficient MV-specific immune response and a transient but profound immunosuppression characterised by a panlymphopenia that occasionally results in opportunistic infections responsible for a high rate of mortality in children. On the basis of in vitro studies, the putative roles of dendritic cells (DCs) in MV infection are discussed. (1) DCs could participate in anti-MV innate immunity because MV turns on TNF-related apoptosis-inducing ligand (TRAIL)-mediated DC cytotoxicity. (2) Cross-priming by non-infected DCs might be the route of MV adaptive immune response. (3) After CD40-ligand activation in secondary lymphoid organs, MV-infected DCs could initiate the formation of Warthin-Finkeldey multinucleated giant cells, replicating MV and responsible for in vivo spreading of MV. (4) We review how integrated viral attack of the host immune system also targets DCs: Progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression observed in vivo is presented and their potential role in lymphopenia is underlined. In conclusion, future research directions are proposed.
Apoptosis↗
Cytotoxic activity of human dendritic cells is differentially regulated by double-stranded RNA and CD40 ligand.
The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-alpha- or IFN-gamma-stimulated CD11c+ blood DCs and IFN-beta-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-beta synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-alpha-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-alpha 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.
Animals↗
Measle virus-infected dendritic cells develop immunosuppressive and cytotoxic activities.
Measle virus (MV) infection induces a transient but profound immunosuppression characterized by a panlymphopenia which occasionally results in opportunistic infections responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DC) in the respiratory mucosa or in the secondary lymphoid organs. After a brief presentation of DCs, we review progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression. In addition, we develop the newly described TRAIL-mediated cytotoxic function of DCs that is turned on by MV infection, but also by interferons or double-stranded RNA (poly (I:C)). Finally, we propose a model where the measles-associated lymphopenia could be mediated by TRAIL and the measles-induced immunosuppression could be transiently prolonged by Fas-mediated destruction of DCs.
Adaptation, Physiological↗
CD40 signaling in human dendritic cells is initiated within membrane rafts.
Despite CD40's role in stimulating dendritic cells (DCs) for efficient specific T-cell stimulation, its signal transduction components in DCs are still poorly documented. We show that CD40 receptors on human monocyte-derived DCs associate with sphingolipid- and cholesterol-rich plasma membrane microdomains, termed membrane rafts. Following engagement, CD40 utilizes membrane raft-associated Lyn Src family kinase, and possibly other raft-associated Src family kinases, to initiate tyrosine phosphorylation of intracellular substrates. CD40 engagement also leads to a membrane raft-restricted recruitment of tumor necrosis factor (TNF) receptor-associated factor (TRAF) 3 and, to a lesser extent, TRAF2, to CD40's cytoplasmic tail. Thus, the membrane raft structure plays an integral role in proximal events of CD40 signaling in DCs. We demonstrate that stimulation of Src family kinase within membrane rafts initiates a pathway implicating ERK activation, which leads to interleukin (IL)-1alpha/beta and IL-1Ra mRNA production and contributes to p38-dependent IL-12 mRNA production. These results provide the first evidence that membrane rafts play a critical role in initiation of CD40 signaling in DCs, and delineate the outcome of CD40-mediated pathways on cytokine production.
CD40 Antigens↗
Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells.
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-alpha 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-1alpha/beta 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.
CD40 Antigens↗
Measles virus induces functional TRAIL production by human dendritic 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 virus-infected dendritic cells are shown to be cytotoxic via the TRAIL pathway.
Apoptosis Regulatory Proteins↗
Consequences of Fas-mediated human dendritic cell apoptosis induced by measles virus.
Mortality from measles virus (MV) infection is caused mostly by secondary infections associated with a pronounced immunosuppression. Dendritic cells (DCs) represent a major target of MV and could be involved in immunosuppression. In this study, human monocyte-derived DCs were used to demonstrate that DC apoptosis in MV-infected DC-T-cell cocultures is Fas mediated, whereas apoptotic T cells could not be rescued by blocking the Fas pathway. Two novel consequences of DC apoptosis after MV infection were demonstrated. (i) Fas-mediated apoptosis of DCs facilitates MV release, while CD40 activation enhances MV replication in DCs. Indeed, detailed studies of infectious MV release and intracellular MV nucleoprotein (NP) showed that inhibition of CD40-CD40L ligand interaction blocks NP synthesis. We conclude that the CD40 ligand expressed by activated T cells first enhances MV replication in DCs, and then Fas ligand produced by activated T cells induces Fas-mediated apoptosis of DCs, thus facilitating MV release. (ii) Not only MV-infected DCs but also bystander uninfected DCs undergo a maturation process confirmed by CD1a, CD40, CD80, CD86, CD83, and major histocompatibility complex type II labeling. The bystander maturation effect results from contact and/or engulfment of MV-induced apoptotic DCs by uninfected DCs. A model is proposed to explain how both a specific immune response and immunosuppression can simultaneously occur after MV infection through Fas-mediated apoptosis and CD40 activation of DCs.
Apoptosis↗
Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells.
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.
Apoptosis↗
Delayed IgG2 humoral response in infants is not due to intrinsic T or B cell defects.
The physiologically low or absent IgG2 responses of infants have been attributed to T or B cell functional immaturity. We have analyzed the capacity of adult and neonatal T lymphocytes to secrete IgG2 switch factor (IgG2-SF) and the capacity of neonatal B cells to respond to such factors. The IgG2-SF capacity was assessed on CD40-activated naive B cells, measuring IgG2 by ELISA in supernatants of cultures performed in the presence of IL-10. T cells secreted IgG2-SF together with IL-2 and IFN-gamma, after activation with a combination of anti-CD2, anti-CD28 and phorbol myristate acetate (Th1-like activation). In contrast, activation with anti-CD3 and anti-CD28, which yielded IL-4 and IL-10 but neither IL-2 nor IFN-gamma (Th2-like activation), did not result in the secretion of IgG2-SF. The supernatant of activated neonatal T cells contained IgG2-SF. Neonates' B cells produced almost as much IgG2 as did naive adult B cells. The effect of IgG2-SF was further demonstrated by its ability to induce 3-15% of CD40-activated naive B cells to express cytoplasmic IgG2 regardless of the presence of IL-10. This study demonstrates that: (i) IgG2 switch can be T cell dependent in humans, (ii) IgG2-SF is produced with Th1-like cytokines and (iii) low IgG2 responses in infants do not result from either an inability of T cells to produce IgG2-SF or an inability of B cells to undergo IgG2 switch in vitro.
Adult↗
CD40-activated human naive surface IgD+ B cells produce IgG2 in response to activated T-cell supernatant.
Human IgG2 is an isotype associated with immune responses to carbohydrates. While interleukin-10 (IL-10) induced CD40-activated naive surface (s)IgD+ human B cells to secrete IgG1 and IgG3, none of 20 recombinant cytokines tested alone, or in combination with IL-10, was able to induce these cells to produce IgG2. This was not due to a specific inability of these sIgD+ B cells, as they could be induced to secrete microgram amounts of IgG2, as well as the three other IgG subclasses, when cultured with an anti-CD3-activated CD4+ T-cell clone. The supernatant of this activated CD4+ T-cell clone contained a soluble factor(s) able to induce the secretion of IgG2 by CD40-activated sIgD+ B cells. Following activation, blood T cells also produced a factor(s) inducing CD40-activated naive B cells to secrete IgG2. This CD4+ T-cell clone will thus permit us ultimately to define the presently uncharacterized cytokine(s) inducing naive B cells to secrete IgG2. This will provide a new insight for the study of immunodeficiencies involving a selective defect in IgG2.
B-Lymphocytes↗
Human interleukin 10 induces naive surface immunoglobulin D+ (sIgD+) B cells to secrete IgG1 and IgG3.
During 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+ (sIgD+) 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 growth-promoting and differentiating activities on human B cells, IL-10 may represent a switch factor for IgG1 and IgG3.
B-Lymphocytes↗
Functional CD40 on B lymphocytes and dendritic cells.
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Antigens, CD↗