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Different pathogens induce different cytokine production via the C-type lectin DC-SIGN. Geijtenbeek and colleagues show that distinct carbohydrates on the pathogen surface induce the assembly and use of distinct DC-SIGN signaling complexes. Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1–CNK–Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens.

The non-pathogenic TH17 subset of helper T cells clears fungal infections, whereas pathogenic TH17 cells cause inflammation and tissue damage; however, the mechanisms controlling these distinct responses remain unclear. Here we found that fungi sensing by the C-type lectin dectin-1 in human dendritic cells (DCs) directed the polarization of non-pathogenic TH17 cells. Dectin-1 signaling triggered transient and intermediate expression of interferon (IFN)-β in DCs, which was mediated by the opposed activities of transcription factors IRF1 and IRF5. IFN-β-induced signaling led to integrin αvβ8 expression directly and to the release of the active form of the cytokine transforming growth factor (TGF)-β indirectly. Uncontrolled IFN-β responses as a result of IRF1 deficiency induced high expression of the IFN-stimulated gene BST2 in DCs and restrained TGF-β activation. Active TGF-β was required for polarization of non-pathogenic TH17 cells, whereas pathogenic TH17 cells developed in the absence of active TGF-β. Thus, dectin-1-mediated modulation of type I IFN responses allowed TGF-β activation and non-pathogenic TH17 cell development during fungal infections in humans.Gringhuis and colleagues show that the extent of type I IFN responses induced by fungal stimulation in human DCs modulate the activation of TGF-β and the production of pathogenic or non-pathogenic TH17 cells.

Gringhuis, Geijtenbeek and colleagues show that the RNA helicase DDX3 binds abortive HIV-1 RNA and induces type I interferon in dendritic cells, a process that is inhibited by the HIV-1-induced activation of kinase PLK1. The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS. Notably, HIV-1 recognition by the C-type lectin receptor DC-SIGN activated the mitotic kinase PLK1, which suppressed signaling downstream of MAVS, thereby interfering with intrinsic host defense during HIV-1 infection. Finally, we showed that PLK1-mediated suppression of DDX3–MAVS signaling was a viral strategy that accelerated HIV-1 replication in infected individuals.

HIV-1 replication requires proviral production of full-length transcripts. Geijtenbeek and colleagues show that early Tat-independent HIV-1 replication coopts innate receptor signaling by DC-SIGN and TLR8 to promote RNA polymerase II elongation complexes at long terminal repeats. Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-κB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1–dependent phosphorylation of the NF-κB subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and dissemination.

Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives TFH formation via crosstalk of RIG-I-like receptor (RLR) RIG-I and MDA5 with type I Interferon (IFN) signaling. DENV infection leads to RLR-dependent IKKε activation, which phosphorylates IFNα/β receptor-induced STAT1 to drive IL-27 production via the transcriptional complex ISGF3. Inhibiting RLR activation as well as neutralizing antibodies against IL-27 prevented TFH formation. DENV-induced CXCR5+PD-1+Bcl-6+ TFH cells secreted IL-21 and activated B cells to produce IgM and IgG. Notably, RLR activation by synthetic ligands also induced IL-27 secretion and TFH polarization. These results identify an innate mechanism by which antibodies develop during viral disease and identify RLR ligands as potent adjuvants for TFH-promoting vaccination strategies.

Helminth parasites control host-immune responses by secreting immunomodulatory glycoproteins. Clinical trials and mouse model studies have demonstrated the potential of helminth-derived glycoproteins for the treatment of immune-related diseases, like allergies and autoimmune diseases. Studies are however hampered by the limited availability of native parasite-derived proteins. Moreover, recombinant protein production systems have thus far been unable to reconstitute helminth-like glycosylation essential for the functionality of some helminth glycoproteins. Here we exploited the flexibility of the N-glycosylation machinery of plants to reconstruct the helminth glycoproteins omega-1 and kappa-5, two major constituents of immunomodulatory Schistosoma mansoni soluble egg antigens. Fine-tuning transient co-expression of specific glycosyltransferases in Nicotiana benthamiana enabled the synthesis of Lewis X (LeX) and LDN/LDN-F glycan motifs as found on natural omega-1 and kappa-5, respectively. In vitro and in vivo evaluation of the introduction of native LeX motifs on plant-produced omega-1 confirmed that LeX on omega-1 contributes to the glycoprotein’s Th2-inducing properties. These data indicate that mimicking the complex carbohydrate structures of helminths in plants is a promising strategy to allow targeted evaluation of therapeutic glycoproteins for the treatment of inflammatory disorders. In addition, our results offer perspectives for the development of effective anti-helminthic vaccines by reconstructing native parasite glycoprotein antigens.

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel.

Strong innate and adaptive immune responses are paramount in combating viral infections. Dendritic cells (DCs) detect viral infections via cytosolic RIG-I like receptors (RLRs) RIG-I and MDA5 leading to MAVS-induced immunity. The DEAD-box RNA helicase DDX3 senses abortive human immunodeficiency virus 1 (HIV-1) transcripts and induces MAVS-dependent type I interferon (IFN) responses, suggesting that abortive HIV-1 RNA transcripts induce antiviral immunity. Little is known about the induction of antiviral immunity by DDX3-ligand abortive HIV-1 RNA. Here we synthesized a 58 nucleotide-long capped RNA (HIV-1 Cap-RNA ) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA induced potent type I IFN responses in monocyte-derived DCs, monocytes, macrophages and primary CD1c DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA induced DC maturation and the expression of pro-inflammatory cytokines. HIV-1 Cap-RNA -stimulated DCs induced proliferation of CD4 and CD8 T cells and differentiated naïve T helper (T ) cells toward a T 2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA resulted in an efficient antiviral innate immune response that reduced ongoing HIV-1 replication in DCs. Our data strongly suggest that HIV-1 Cap-RNA induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.

Effective immune responses depend on the recognition of pathogens by dendritic cells (DCs) through pattern recognition receptors (PRRs). These receptors induce specific signaling pathways that lead to the induction of immune responses against the pathogens. It is becoming evident that C-type lectins are also important PRRs. In particular, the C-type lectin DC-SIGN has emerged as a key player in the induction of immune responses against numerous pathogens by modulating TLR-induced activation. Recent reports have begun to elucidate the molecular mechanisms underlying these immune responses. Upon pathogen binding, DC-SIGN induces an intracellular signaling pathway with a central role for the serine/threonine kinase Raf-1. For several pathogens that interact with DC-SIGN, including Mycobacterium tuberculosis and HIV-1, Raf-1 activation leads to acetylation of NF-κB subunit p65, which induces specific gene transcription profiles. In addition, other DC-SIGN-ligands induce different signaling pathways downstream of Raf-1, indicating that DC-SIGN-signaling is tailored to the pathogen. In this review we will discuss in detail the current knowledge about DC-SIGN signaling and its implications on immunity.

Key Points C-type lectin receptors (CLRs) are efficient pattern-recognition receptors (PRRs) that interact with pathogens via carbohydrate structures, leading to enhanced antigen presentation as well as modulation of T helper cell (T H cell) differentiation, collectively inducing pathogen-tailored adaptive immune responses. Crosstalk between innate signalling by CLRs and other PRRs, as well as other receptors such as type I interferon receptor (IFNAR), enhances the diversity of T H cell responses to pathogens. Engagement of the CLR dectin 1 by fungi induces various intracellular signalling pathways that cooperate to induce efficient T H 1 and T H 17 cell responses, which are crucial for antifungal immunity. DC-SIGN (DC-specific ICAM3-grabbing non-integrin), another CLR, induces specific signalling cascades for distinct pathogens, according to the carbohydrate ligand recognized. The recognition of mannose on intracellular pathogens such as fungi, viruses and mycobacteria leads to protective T H 1 cell responses when triggered together with Toll-like receptor (TLR) signalling. By contrast, parasitic fucose-containing ligands induce both T H 2 and T follicular helper (T FH ) cell responses (which are necessary for humoral immunity) during crosstalk of DC-SIGN signalling with TLR and IFNAR signalling. CLR triggering also contributes to pathogenic disorders; dectin 2 engagement by allergens originating from fungi or house dust mites leads to allergic T H 2 cell responses, whereas triggering of macrophage-inducible C-type lectin receptor (MINCLE) by pathogenic Fonsecaea spp. fungi represses T H 1 cell responses, thereby promoting fungal dissemination. CLRs have previously been used in vaccine strategies for their antigen-processing capacity. Our advanced knowledge of the signalling pathways by which CLRs direct adaptive immunity now provides a powerful tool to add a novel level of sophistication to the design of vaccines. In particular, the very specific T FH cell responses that are induced by CLRs such as DC-SIGN and CLEC9A could greatly improve the generation of broadly neutralizing antibodies against viruses such as HIV-1. Here, the authors discuss the role of C-type lectin receptor signalling pathways in the control of T helper cell differentiation and examine how these receptors and pathways can be harnessed for vaccine strategies. Pathogen recognition by C-type lectin receptors (CLRs) expressed by dendritic cells is important not only for antigen presentation, but also for the induction of appropriate adaptive immune responses via T helper (T H ) cell differentiation. CLRs act either by themselves or in cooperation with other receptors, such as other CLRs, Toll-like receptors and interferon receptors, to induce signalling pathways that trigger specialized cytokine programmes for polarization of T H cell differentiation. In this Review, we discuss how triggering of the prototypical CLRs leads to distinct pathogen-tailored T H cell responses and how we can harness our expanding knowledge for vaccine design and the treatment of inflammatory and malignant diseases.