Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Abstract

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.

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

“…Thus, it is unsurprising that many pathogens have developed mechanisms to modulate and disable DCs (1,6,33,40,(45)(46)(47)(48). One way in which pathogens interfere with host immune responses, including those mediated by DCs, is manipulation of normal host systems meant to limit hyperresponsiveness to microbial products, resulting in control of inflammation.…”

Characterization of novel safe lentiviral vectors derived from simian immunodeficiency virus (SIVmac251) that efficiently transduce mature human dendritic cells

“…Both lentiviral and retroviral vectors, generated as VSV-G-pseudotyped particles, had similar titers on proliferating cells (around 5 × 10 6 TU/ml) and were used to infect human DCs with a low MOI, of one infectious particle per target cell (Figure 4b). Infected immature DCs were then co-cultured either with irradiated mouse fibroblasts expressing the human CD40 ligand, to allow their differentiation into mature DCs, 51 or with irradiated mouse fibroblasts expressing the human CD32, as control. GFP expression was measured 3 days after transduction and the mature DC phenotype of the GFP-positive cells was ascertained by immunostaining of MHC class II molecules and FACS analysis (Figure 4b and c).…”

“…DCs were infected in the presence of 6 g of polybrene/ml for 4 h at 37°C, then washed and incubated for 48 h in normal DC medium in the presence of 2 × 10 4 irradiated (7000 rads) fibroblastic CD40 ligand-or CD32-transfected L mouse cells (both kindly provided by Schering-Plough Laboratory for Immunological Research) to allow, or not allow, differentiation into mature DCs, respectively. 51 To rule out pseudo-transduction by free GFP or by GFP-containing pseudo-particles or by DNA plasmids released by the producer cells and ingested by the DCs, experiments were performed in duplicate in the absence or the presence of 10 m AZT (3Ј-azido-3Ј-deoxythymidine; SigmaAldrich, Saint Quentin Fallavier, France), an inhibitor of reverse transcriptase, which was added 60 min before infection until transduction analysis. Transduction efficiency was then assessed by FACS analysis 2 and 5 days after infection.…”

Measles virus modulates chemokine release and chemotactic responses of dendritic cells

“…MV targets CD150 + haematopoetic cells (Condack et al, 2007; de Swart et al, 2007), and in experimentally infected macaques, mucosal DCs replicate MV in vivo (de Swart et al, 2007). DCs are generated from precursors and they mature upon MV exposure in vitro (Dubois et al, 2001;Fugier-Vivier et al, 1997;Grosjean et al, 1997;Kaiserlian et al, 1997;Schnorr et al, 1997;Servet-Delprat et al, 2000), this involves toll-like receptor (TLR) signalling and type I interferon (IFN) (Minagawa et al, 2001;Schnorr et al, 1997;Servet-Delprat et al, 2000;Shingai et al, 2007). MV-matured DCs (MV-DCs) fail to promote allogenic T cell expansion, which results from signalling by the viral glycoproteins expressed on the DC surface to T cells (Kerdiles et al, 2006;Schneider-Schaulies & Dittmer, 2006;Schneider-Schaulies et al, 2003;Servet-Delprat et al, 2003).…”