Fungal sensing by dectin-1 directs the non-pathogenic polarization of T17 cells through balanced type I IFN responses in human DCs.

The non-pathogenic T17 subset of helper T cells clears fungal infections, whereas pathogenic T17 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 T17 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.

Crosstalk between R848 and abortive HIV-1 RNA-induced signaling enhances antiviral immunity.

Pathogens trigger multiple pattern recognition receptors (PRRs) that together dictate innate and adaptive immune responses. Understanding the crosstalk between PRRs is important to enhance vaccine efficacy. Abortive HIV-1 RNA transcripts are produced during acute and chronic HIV-1 infection and are known ligands for different PRRs, leading to antiviral and proinflammatory responses.

Abortive HIV-1 RNA induces pro-IL-1β maturation via protein kinase PKR and inflammasome activation in humans.

The proinflammatory cytokine IL-1β mediates high levels of immune activation observed during acute and chronic human immunodeficiency virus 1 (HIV-1) infection. Little is known about the mechanisms that drive IL-1β activation during HIV-1 infection. Here, we have identified a crucial role for abortive HIV-1 RNAs in inducing IL-1β in humans.

Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4 T Cell Infection in HIV-1-Infected Individuals.

The mitochondrial antiviral protein MAVS is a key player in the induction of antiviral responses; however, human immunodeficiency virus 1 (HIV-1) is able to suppress these responses. Two linked single nucleotide polymorphisms (SNPs) in the gene render MAVS insensitive to HIV-1-dependent suppression, and have been shown to be associated with a lower viral load at set point and delayed increase of viral load during disease progression. Here, we studied the underlying mechanisms involved in the control of viral replication in individuals homozygous for this genotype.

Synthetic Abortive HIV-1 RNAs Induce Potent Antiviral Immunity.

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.

DDX3 in HIV-1 infection and sensing: A paradox.

HIV-1 sensors and their signaling features have been an ongoing topic of intense research over the last decade, as these mechanisms fail to establish protective immunity against HIV-1. Here, we discuss how HIV-1 infects dendritic cells (DCs) and which sensors play a role in recognizing viral DNA and RNA in these specialized immune cells. We will elaborate on the RNA helicase DDX3, which is crucial in translation initiation of HIV-1 mRNA, but also fulfills an important role as RNA sensor and inducer of antiviral immunity in DCs.

RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production.

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.

RIG-I-like Receptor Triggering by Dengue Virus Drives Dendritic Cell Immune Activation and T1 Differentiation.

Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses.

Production and glyco-engineering of immunomodulatory helminth glycoproteins in plants.

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.

HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3.

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.

Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets.

The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection.

C-type lectin receptors in the control of T helper cell differentiation.

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 (TH) 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 TH cell differentiation. In this Review, we discuss how triggering of the prototypical CLRs leads to distinct pathogen-tailored TH cell responses and how we can harness our expanding knowledge for vaccine design and the treatment of inflammatory and malignant diseases.

SAMHD1 degradation enhances active suppression of dendritic cell maturation by HIV-1.

A hallmark of HIV-1 infection is the lack of sterilizing immunity. Dendritic cells (DCs) are crucial in the induction of immunity, and lack of DC activation might underlie the absence of an effective anti-HIV-1 response. We have investigated how HIV-1 infection affects maturation of DCs.

Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production.

Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (TFH) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKε, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3.

Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases.

Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly regulated at various steps, including dephosphorylation by PP1 phosphatases, which induces their activation.

Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5.

The cytosolic sensor MDA5 is crucial for antiviral innate immune defense against various RNA viruses including measles virus; as such, many viruses have evolved strategies to antagonize the antiviral activity of MDA5. Here, we show that measles virus escapes MDA5 detection by targeting the phosphatases PP1α and PP1γ, which regulate MDA5 activity by removing an inhibitory phosphorylation mark. The V proteins of measles virus and the related paramyxovirus Nipah virus interact with PP1α/γ, preventing PP1-mediated dephosphorylation of MDA5 and thereby its activation.

Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation.

Carbohydrate-specific signalling through DC-SIGN provides dendritic cells with plasticity to tailor immunity to the nature of invading microbes. Here we demonstrate that recognition of fucose-expressing extracellular pathogens like Schistosoma mansoni and Helicobacter pylori by DC-SIGN favors T helper cell type-2 (TH2) responses via activation of atypical NF-κB family member Bcl3. Crosstalk between TLR and DC-SIGN signalling results in TLR-induced MK2-mediated phosphorylation of LSP1, associated with DC-SIGN, upon fucose binding.

Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity.

Recognition of fungal pathogens by C-type lectin receptor (CLR) dectin-1 on human dendritic cells is essential for triggering protective antifungal TH1 and TH17 immune responses. We show that Fonsecaea monophora, a causative agent of chromoblastomycosis, a chronic fungal skin infection, evades these antifungal responses by engaging CLR mincle and suppressing IL-12, which drives TH1 differentiation. Dectin-1 triggering by F.

C-type lectin receptors orchestrate antifungal immunity.

Fungal infections are an emerging threat for human health. A coordinated host immune response is fundamental for successful elimination of an invading fungal microbe. A panel of C-type lectin receptors expressed on antigen-presenting dendritic cells enable innate recognition of fungal cell wall carbohydrates and tailors adaptive responses via the instruction of CD4⁺ T helper cell fates.

An evolutionary perspective on C-type lectins in infection and immunity.

Host-pathogen interactions have coevolved for many years. On the one hand, the human immune system consists of innate and adaptive immune cells that function to defeat pathogens, and on the other hand, pathogens have coevolved to use the system for their own propagation. C-type lectins are conserved receptors recognizing carbohydrate structures on viruses, bacteria, parasites, and fungi.

Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome.

Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk.

Innate signaling in HIV-1 infection of dendritic cells.

Purpose Of Review: This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure.

Recent Findings: HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells.

Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2.

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of T(H)1 and T(H)-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 T(H)-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of T(H)-17-polarizing cytokines IL-1β and IL-23p19.