IL-4 Suppresses Dendritic Cell Response to Type I Interferons

Laboratory of Dendritic Cell Biology, Joseph Stokes Jr. Research Institute, Division of Rheumatology, Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2007; 179(10):6446-55. DOI: 10.4049/jimmunol.179.10.6446
Source: PubMed


Cytokines play an important role in modulating the development and function of dendritic cells (DCs). Type I IFNs activate DCs and drive anti-viral responses, whereas IL-4 is the prototype of a Th2 cytokine. Evidence suggests that type I IFNs and IL-4 influence each other to modulate DC functions. We found that two type I IFNs, IFN-alpha and IFN-beta, stimulated a similar costimulatory profile in myeloid resting DCs. IL-4 suppressed the response of myeloid DCs to both type I IFNs in vitro and in vivo by impairing the up-regulation of MHC and costimulatory molecules and the production of cytokines, such as IL-6 and IL-15, and anti-viral genes, such as Mx-1, upon type I IFN stimulation. In dissecting the mechanism underlying this inhibition, we characterized the positive feedback loop that is triggered by IFN-alpha in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-alpha and -beta receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-beta, and the IFNARs in vitro and in vivo. Therefore, IL-4 renders myeloid DCs less responsive to paracrine type I IFNs and less potent in sustaining the autocrine positive loop that normally amplifies the effects of type I IFNs. This inhibition could explain the increased susceptibility to viral infections observed during Th2-inducing parasitoses.

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Available from: Chhanda Biswas
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    • "In both humans and mice, stimulation of TLR7 and TLR9 results in vigorous production of multiple pro-inflammatory cytokines such as IL-6, IL-12 and TNFα [45]. We have shown in a previous report that IL-6 is highly induced by Type I IFN stimulation, particularly by IFNβ and that IL-4 inhibits IL-6 production [29]. We analyzed the gene expression of IL-6, the two subunits of IL-12, IL-12p35 and IL-12p40, as well as TNFα in cDCs that were treated or not with IL-4 for 24 hours and then stimulated with CpG or R848 for 6 hours. "
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    ABSTRACT: Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNβ and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFα, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFκB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6-dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, -2 and -3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV-based lentivirus. Our results indicate that IL-4 modulates and counteracts pro-inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Additionally, treatment with IFN-α or a TLR agonist was shown to differentially modulate DC maturation and immune function. In comparison to LPS stimulation, IFN-α was proposed to only partially affect DC maturation [61,62] while also inhibiting the production of IL-12 and thus potentially skewing the T helper response [63,64]. However, IFN-α is considered as a major regulator of the antiviral response and has been shown to be a potent inducer of CD8+T cell cross-priming and therefore critically required to induce DC full maturation upon engagement of a TLR [65-67]. "
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    ABSTRACT: Background Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells to encounter disseminating pathogens. The cellular restriction factor BST-2/tetherin (also known as CD317 or HM1.24) potently restricts HIV-1 release by retaining viral particles at the cell surface in many cell types, including primary cells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immature dendritic cells. Results We now report that BST-2/tetherin expression in myeloid (myDC) and monocyte-derived dendritic cells (DC) can be significantly up-regulated by IFN-α treatment and TLR-4 engagement with LPS. In contrast to HeLa or 293T cells, infectious HIV-1 release in immature DC and IFN-α–matured DC was only modestly affected in the absence of Vpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excluded from HIV containing tetraspanin-enriched microdomains (TEMs) in both immature DC and IFN-α–matured DC. In contrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection to CD4+ T cells. Additionally, LPS, but not IFN-α stimulation of immature DC, leads to a dramatic redistribution of cellular restriction factors to the TEM as well as at the virological synapse between DC and CD4+ T cells. Conclusions In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates the intrinsic antiviral activity of BST-2/tetherin, during cis-infection of CD4+ T cells across the DC/T cell virological synapse. Manipulating the function and potency of cellular restriction factors such as BST-2/tetherin to HIV-1 infection, has implications in the design of antiviral therapeutic strategies.
    Full-text · Article · Jan 2013 · Retrovirology
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    • "Cytokine production is another important mediator of innate immunity, considerably affected by bystander chronic infections. IFN-a/b responses by dendritic cells (DCs) and macrophages, crucial for early antiviral control, are inhibited by IL-4 and IL-10 (Varano et al., 2000; Sriram et al., 2007), a mechanism potentially relevant for the increased viral replication during coinfection with Th2- inducing parasites. Furthermore, production of the Th1 cytokine IL-1 by myeloid cells is suppressed by type I and type II IFN, providing a potential mechanism for the regulation of Mtb immunity by viral or other Th1-inducing coinfections (Mayer-Barber et al., 2011). "
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    ABSTRACT: Chronic infections with persistent pathogens such as helminths, mycobacteria, Plasmodium, and hepatitis viruses affect more than a third of the human population and are associated with increased susceptibility to other pathogens as well as reduced vaccine efficacy. Although these observations suggest an impact of chronic infections in modulating immunity to unrelated antigens, little is known regarding the underlying mechanisms. Here, we summarize evidence of the most prevalent infections affecting immunity to unrelated pathogens and vaccines, and discuss potential mechanisms of how different bystander chronic infections might impact immune responses. We suggest that bystander chronic infections affect different stages of host responses and may impact transmission and recognition of other pathogens, innate immune responses, priming and differentiation of adaptive effector responses, as well as the development and maintenance of immunological memory. Further understanding of the immunological effects of coinfection should provide opportunities to enhance vaccine efficacy and control of infectious diseases.
    Preview · Article · Oct 2012 · Cell host & microbe
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