Human pDCs Research Articles

Synthetic oligoribonucleotides-containing secondary structures act as agonists of Toll-like receptors 7 and 8

Single-stranded RNAs act as ligands of Toll-like receptors (TLRs) 7 and 8 and induce immune responses. In the present study, we have designed and synthesized phosphorothioate oligoribonucleotides (ORNs) with self-complementary sequences that form duplex structures with either 3′- or 5′-overhanging sequences. We studied the new ORNs for their duplex formation, nuclease stability, and ability to induce immune-stimulatory activate through TLR7 and TLR8 in TLR-transfected cell lines, human PBMCs, human pDCs, and in vivo in mice. Thermal melting and gel electrophoresis studies showed that all ORNs formed secondary structures and that the thermal stability of the duplex is depended on the length and GC composition of the duplex. Nuclease stability of ORNs increased with increasing thermal stability of the duplex formed. All ORN showed TLR8 activity in HEK293 cells, and induced cytokine and chemokine production in human PBMC cultures. In addition to TLR8 activity, two ORNs containing a ‘CUGAAUU’ motif in the duplex-forming region induced immune stimulation through TLR7 in HEK293 cells, human PBMC and pDC cultures, and in vivo in mice. These results suggest that secondary structures in ORN provide nuclease stability and lead to stimulation of immune responses through TLR8 as well as TLR7 depending on the presence of specific nucleotide motifs.

Cigarette smoke attenuates the production of cytokines by human plasmacytoid dendritic cells and enhances the release of IL-8 in response to TLR-9 stimulation

Myeloid and plasmacytoid dendritic cells (mDCs, pDC) are crucial to the immune system, detecting microorganisms and linking the innate and adaptive immunity. pDC are present in small quantities in tissues that are in contact with the external environment; mainly the skin, the inner lining of the nose, lungs, stomach and intestines. They produce large amounts of IFN-α after stimulation and are pivotal for the induction of antiviral responses. Chronic obstructive pulmonary disease (COPD) patients are known to be more susceptible to viral infections. We have demonstrated that exposure of mDC to cigarette smoke extract (CSE) leads to the release of chemokines, however, not much is known about the role of pDC in COPD. In this study, we addressed several key questions with respect to the mechanism of action of CSE on human pDC in an in vitro model. Human pDCs were isolated from normal healthy volunteers and subjected to fresh CSE and the levels of IL-8, TNF-α, IP-10, IL-6, IL-1, IL-12 and IL-10 and IFN-α were studied by both ELISA and real time PCR methods. We observed that CSE augmented the production of IL-8 and suppressed the release of TNF-α, IL-6 and IFN-α. Moreover, CSE suppressed PI3K/Akt signalling in pDC. In conclusion, our data indicate that CSE has both the potential to diminish anti-viral immunity by downregulating the release of IFN-α and other pro-inflammatory cytokines while, at the same time, augmenting the pathogenesis of COPD via an IL-8 induced recruitment of neutrophils.

CD2 Distinguishes Two Subsets of Human Plasmacytoid Dendritic Cells with Distinct Phenotype and Functions

Plasmacytoid dendritic cells (pDCs) are key regulators of antiviral immunity. They rapidly secrete IFN-alpha and cross-present viral Ags, thereby launching adaptive immunity. In this study, we show that activated human pDCs inhibit replication of cancer cells and kill them in a contact-dependent fashion. Expression of CD2 distinguishes two pDC subsets with distinct phenotype and function. Both subsets secrete IFN-alpha and express granzyme B and TRAIL. CD2(high) pDCs uniquely express lysozyme and can be found in tonsils and in tumors. Both subsets launch recall T cell responses. However, CD2(high) pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.

Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex

The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well-organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. Both hE2 and hBP consist of three well defined domains, namely the lipoyl domain, the subunit-binding domain and the inner domain, connected with flexible linkers. hE1 (α 2β 2) binds to the subunit-binding domain of hE2; whereas hE3 binds to the E3-binding domain of hBP. Among several residues of the C-terminal surface of the hE1β, E1βD289 was found to interact with hE2K276. The C-terminal residue I329 of the hE1β did not participate in binding to hE2. This latter finding shows specificity in the interaction between E1β and E2 in hPDC. The selective binding between hE3 and the E3-binding domain of hBP was investigated using specific mutants. E3R460G and E3340K showed significant reductions in affinity for hBP as determined by surface plasmon resonance. Both residues are involved in the structural organization of the binding site on hE3. Substitution of I157, N137 and R155 of hBP resulted in variable increases in the K D for binding with wild-type hE3, suggesting that the binding results from several weak electrostatic bonds and hydrophobic interactions among residues of hBP with residues at the interface of dimeric hE3. These results provide insight in the mono-specificity of binding of E1 to E2 and E3 to BP in hPDC and showed the differences in the binding of peripheral components (E1 and E3) in human and bacterial PDCs.

Molecular characterization of human plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) represent a unique and important immune cell population capable of producing large quantifies of type I interferon (IFN) in response to viruses as well as nucleic acid-containing complexes from the host. These rare and mysterious cells have been revealed by in-depth molecular characterization. Several innate sensors and signaling molecules enriched in pDCs allow their specialized innate immune functions. In addition, human pDCs use a group of surface receptors that, through activation of a B-cell receptor (BCR)-like signaling pathway, modulate type I IFN responses. It is clear now that pDC development is influenced by distinctive transcription factors that specify a unique lineage. CD4(+)CD56(+) hematodermic neoplasm of human pDC origin has been revealed in explicit molecular terms. A detailed molecular description of pDCs helps us better define, understand, and track human pDCs in relation to their functions and physiological involvement.

Developmental regulation of MHC II expression and transport in human plasmacytoid-derived dendritic cells

AbstractPlasmacytoid predendritic cells (pDCs) play a key role in antiviral immunity through their capacity to produce large amounts of type I interferons in response to Toll-like receptor triggering, and to differentiate into dendritic cells (DCs). However, their antigen processing and presentation pathways remain poorly characterized. In this study, we analyzed major histocompatibility complex class II (MHC II) synthesis and transport in primary human pDCs. We show that stimulation of pDCs with influenza virus leads to a sustained neosynthesis of MHC II molecules, which rapidly accumulate in antigen loading compartments organized around the microtubule organization center. MHC II endocytosis as well as antigen internalization remain active during the entire process of pDC differentiation into DCs, suggesting a capacity to constantly renew surface peptide–MHC II complexes. Formation of the intracellular pool of MHC II in activated pDCs is nuclear factor-κB–dependent and associated with acquisition of a dendritic phenotype, but independent of the IRF7-type I interferon-dependent pathway, suggesting that innate and adaptive functions of pDCs are differentially regulated. Our data demonstrate that the regulation of MHC II expression and transport is drastically different in pDCs compared with conventional DCs, indicating distinct and potentially complementary immunoregulatory functions.

TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1β and caspase-1 in monocytes and dendritic cells

TLRs represent the first line of defense against invading pathogens in the innate immune system. Certain cytokines are important mediators and essentially necessary to assure an appropriately regulated immune response. Recent data gave initial evidence that IL-1β is one of the most relevant members of these regulating cytokines. We investigated the induction of IL-1β production in monocytes and pDCs stimulated with ligands for TLR7 and TLR8 and with antiphospholipid antibodies (aPL). Using human monocytes and pDCs for stimulation with specific TLR7 and TLR8 ligands such as resiquimod (R848) and single stranded RNA (RNA42) as well as with a human monoclonal aPL HL5B resulted in a specific upregulation of IL-1β mRNA and protein in these cells. Determination of expression-levels using real-time RT-PCR showed significantly augmented TLR-dependent IL-1β and caspase-1 expression. This increase could be substantially enhanced by adding the monoclonal aPL HL5B. To demonstrate the direct dependency between TLR stimulation and IL-1β production, specific TLR inhibitors were applied and the IL-1β and caspase-1 secretion could be explicitly decreased. The respective protein levels were determined using Western Blot, FACS analysis or ELISA assays. In conclusion we demonstrated that the downstream signaling pathway of TLR7 and TLR8 in monocytes and pDCs after stimulation with specific ligands included not only the secretion of cytokines such as TNFα and IL-1β but as well the activation of necessary regulating proteins like caspase-1. APL seem to enforce this process hinting that endogenous stimulation of TLRs in the Antiphospholipid Syndrome (APS) patients resulted in enhanced secretion of proinflammatory cytokines.

Regulation of cytokine expression in human plasmacytoid dendritic cells by prostaglandin I2analogues

Plasmacytoid dendritic cells (pDCs) are critical in controlling adaptive immunity, but the mechanisms governing cytokine expression remain incompletely defined. Analogues of prostaglandin (PG)I(2), such as iloprost, can modulate functions of myeloid dendritic cells, but their involvement in the regulation of human pDCs remains unknown. To this end, the regulatory role of PGI(2) analogues on cytokine expression in pDCs was investigated. Circulating pDCs were magnetically sorted with BDCA-4 cell isolation kits from human peripheral blood mononuclear cells and treated with varying concentrations of iloprost with or without the addition of Toll-like receptor agonists, or an I prostanoid (IP) receptor antagonist, CAY10449. The levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-alpha and interleukin (IL)-10 were measured by ELISA. Iloprost induced IL-10 expression, but suppressed CpG oligodeoxynucleotide- (or imiquimod-) induced TNF-alpha and IFN-alpha production in pDCs. This effect was reversed by the addition of CAY10449. Forskolin, a cyclic adenosine monophosphate activator, conferred a similar modulating effect to that noted in iloprost-treated pDCs, although a higher concentration of forskolin was required to exert the same effect. Iloprost enhanced interleukin-10 and suppressed Toll-like receptor-mediated tumour necrosis factor-alpha and interferon-alpha production of human plasmacytoid dendritic cells via the I prostanoid receptor and, in part, the cyclic adenosine monophosphate pathway.

Toll-like receptor 9 expression and interferon-α secretion upon CpG-ODN stimulation in allergic subjects

Purpose:The aim of this study is to explore the effect of the Toll-like receptor 9 (TLR9) expressed in plasmacytoid dendritic cells (pDCs) that respond to antigen to Th2 immune deviation in allergic patients. Methods:Subjects consisted of 19 allergic patients and 17 healthy volunteers. Skin prick tests and nasal provocation tests were performed for the two groups. Peripheral blood mononuclear cells (PBMCs) were collected from subjects and analyzed for the Lineage Cocktail (CD3, CD14, CD16, CD19, CD20, CD56) (-), HLA-DR (+), and CD123 (+) using flow cytometry. In addition, we analyzed TLR9 mRNA by reverse transcriptase-polymerase chain reaction. The level of interferon (IFN) of the PBMCs following stimulation with the TLR9 ligand CpG-ODN 2216 was also evaluated. Results:Analyses of CD123 (+) revealed a nearly similar distribution for the classical pDC markers in the allergic group (0.1%0.04%) and in the controls (0.25%0.23%). The mRNA levels of TLR9 on PBMCs were not different between the allergic group and the controls (1.290.41 vs. 1.250.23, respectively). Additionally, the level of IFN in PBMCs exposed to stimuli of the TLR9 ligand CpG-ODN 2216 was not significantly different between the two groups (911829 vs. 1,095 888 pg/mL, respectively). Conclusion:We found no evidence that TLR9-dependent immune responses in human pDCs are associated with allergic status.

HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase–dependent mechanism

Plasmacytoid DCs (pDCs) have been implicated as crucial cells in antiviral immune responses. On recognizing HIV, they become activated, secreting large amounts of IFN-alpha and inflammatory cytokines, thereby potentiating innate and adaptive antiviral immune responses. Here, we have shown that HIV-stimulated human pDCs can also induce the differentiation of naive CD4+ T cells into Tregs with suppressive function. This differentiation was independent of pDC production of IFN-alpha and primarily dependent on pDC expression of indoleamine 2,3-dioxygenase, which was induced through the TLR/MyD88 pathway, following binding of HIV to CD4 and triggering of TLR7 by HIV genomic RNA. Functionally, the Tregs induced by pDCs were shown to inhibit the maturation of bystander conventional DCs. This study therefore reveals what we believe to be a novel mechanism by which pDC may regulate and potentially limit anti-HIV immune responses.

TLR9/TLR7-triggered downregulation of BDCA2 expression on human plasmacytoid dendritic cells from healthy individuals and lupus patients

Plasmacytoid dendritic cells (pDCs) can produce a large amount of interferon-alpha (IFN-α) upon exposure to TLR9 or TLR7 agonists. Human pDCs have been shown to play an important role in the pathogenesis of systemic lupus erythematosus (SLE) through increased production of IFN-α. So, how to negatively regulate activation of pDCs and how to evaluate the activation of pDC in SLE patients attract much attention. BDCA2 is selectively expressed on human pDCs, acting as a hallmark of human pDCs. In this study, we showed that BDCA2 expression on pDCs decreased along maturation of pDCs, and TLR7 or TLR9 agonists could further significantly downregulate pDCs to express BDCA2, suggesting that the activated pDCs exhibit decreased expression of BDCA2. Functionally, BDCA2 ligation significantly inhibited upregulation of CD40, CD86 and CCR7 expression, IFN-α, IFN-β and IL-6 production by pDCs stimulated with CpG ODN. Moreover, BDCA2 ligation suppressed CpG ODN-activated pDCs to mediate Th1 response, including T cell proliferation, IFN-γ production, and CD4 +CCR5 +Th1 development, confirming that BDCA2 is a negative regulator of TLR9-dependent activation of human pDCs. BDCA2 expression on pDCs from SLE patients decreased significantly but IFN-α production of these patients increased markedly as compared to that from healthy donors. Therefore, these results suggest that downregulation of BDCA2 expression on pDCs may reflect the activation of pDCs accumulated in SLE patients, and may be one marker for indication of the disease activity of SLE patients.

Effect of Bacillus anthracis virulence factors on human dendritic cell activation

Bacillus anthracis possesses three primary virulence factors: capsule, lethal toxin (LT), and edema toxin (ET). Dendritic cells (DCs) are critical to innate and acquired immunity and represent potential targets for these factors. We examined the ability of B. anthracis spores and bacilli to stimulate human monocyte-derived DC (MDDC), primary myeloid DC (mDC), and plasmacytoid DC (pDC) cytokine secretion. Exposure of MDDCs and mDCs to spores or vegetative bacilli of the genetically complete strain UT500 induced significantly increased cytokine secretion. Spores lacking genes required for capsule biosynthesis stimulated significantly higher cytokine secretion than UT500 spores from mDCs, but not MDDCs. In contrast, bacilli lacking capsule stimulated significantly higher cytokine secretion than UT500 bacilli in both MDDCs and mDCs. Spores or bacilli lacking both LT and ET stimulated significantly higher cytokine secretion than UT500 spores or bacilli, respectively, in both mDCs and MDDCs. pDCs exposed to spores or bacilli did not produce significant amounts of cytokines even when virulence factors were absent. In conclusion, B. anthracis employs toxins as well as capsule to inhibit human MDDC and mDC cytokine secretion, whereas human pDCs respond poorly even when capsule or both toxins are absent.

Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-α production

AbstractC-type lectin receptors (CLRs) fulfill multiple functions within the immune system by recognition of carbohydrate moieties on foreign or (altered) self-structures. CLRs on myeloid dendritic cells (DCs) have been well characterized as pattern-recognition receptors (PRRs) combining ligand internalization with complex signaling events. Much less is known about CLR expression and function in human plasmacytoid DCs (pDCs), the major type I interferon (IFN) producers. In this study, we demonstrate that, next to the CLR BDCA-2, human pDCs express DC immunoreceptor (DCIR), a CLR with putative immune-inhibitory function, but not dectin-1, mannose receptor, or DC-specific ICAM-3–grabbing nonintegrin. DCIR surface levels are reduced on pDC maturation after TLR9 triggering. Interestingly, DCIR triggering inhibits TLR9-induced IFN-α production while leaving up-regulation of costimulatory molecule expression unaffected. Furthermore, DCIR is readily internalized into pDCs after receptor triggering. We show that DCIR internalization is clathrin-dependent because it can be inhibited by hypertonic shock and dominant-negative dynamin. Importantly, antigens targeted to pDCs via DCIR are presented to T cells. These findings indicate that targeting DCIR on pDCs not only results in efficient antigen presentation but also affects TLR9-induced IFN-α production. Collectively, the data show that targeting of DCIR can modulate human pDC function and may be applied in disease preven-tion and treatment.

Novel markers of normal and neoplastic human plasmacytoid dendritic cells

AbstractPlasmacytoid dendritic cells (pDCs) are involved in innate immunity (eg, by secreting interferons) and also give rise to CD4+CD56+ hematodermic neoplasms. We report extensive characterization of human pDCs in routine tissue samples, documenting the expression of 19 immunohistologic markers, including signaling molecules (eg, BLNK), transcription factors (eg, ICSBP/IRF8 and PU.1), and Toll-like receptors (TLR7, TLR9). Many of these molecules are expressed in other cell types (principally B cells), but the adaptor protein CD2AP was essentially restricted to pDCs, and is therefore a novel immunohistologic marker for use in tissue biopsies. We found little evidence for activation-associated morphologic or phenotypic changes in conditions where pDCs are greatly increased (eg, Kikuchi disease). Most of the molecules were retained in the majority of pDC neoplasms, and 3 (BCL11A, CD2AP, and ICSBP/IRF8) were also commonly negative in leukemia cutis (acute myeloid leukemia in the skin), a tumor that may mimic pDC neoplasia. In summary, we have documented a range of molecules (notably those associated with B cells) expressed by pDCs in tissues and peripheral blood (where pDCs were detectable in cytospins at a frequency of < 1% of mononuclear cells) and also defined potential new markers (in particular CD2AP) for the diagnosis of pDC tumors.

P2Y receptor signaling regulates phenotype and IFN-α secretion of human plasmacytoid dendritic cells

AbstractPlasmacytoid dendritic cells (PDCs) play powerful regulatory roles in innate and adaptive immune responses and are a major source of type I interferon (IFN) following viral infection. During inflammation and mechanical stress, cells release nucleotides into the extracellular space where they act as signaling molecules via G protein–coupled P2Y receptors. We have previously reported on the regulation of myeloid dendritic cell (DC) function by nucleotides. Here, we report that human PDCs express several subtypes of P2Y receptors and mobilize intracellular calcium in response to nucleotide exposure. As a functional consequence, PDCs acquire a mature phenotype that is further enhanced in the context of CD40 ligation. Strikingly, nucleotides strongly inhibit IFN-α secretion induced by influenza virus or CpG-A. This effect is most pronounced for the uridine nucleotides UDP and UTP and the sugar nucleotide UDP-glucose, ligands of P2Y6, P2Y4, and P2Y14, respectively. Nucleotide-induced inhibition of IFN-α production is blocked by suramin, a P2Y receptor antagonist. Pharmacological data point toward a role of protein kinase C in the negative regulation of type I IFN. Manipulating PDC function with P2Y receptor agonists may offer novel therapeutic strategies for autoimmune diseases or cancer.

Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon‐α via toll‐like receptor 9

High-affinity IgE receptor (Fc epsilon RI) expression on blood dendritic cells reportedly correlates with serum IgE levels. Our studies demonstrate that plasmacytoid dendritic cells (pDCs) secrete pro-inflammatory cytokines (IL-6, TNF-alpha) following Fc epsilon RI stimulation - a mode of activation that simultaneously reduces expression of Toll-like receptor 9 (TLR9). Whether or not TLR9 and/or Fc epsilon RI levels and their function on dendritic cells relate to allergic status is unknown. The aim of this study is to compare the innate (TLR9-mediated) immune response of human pDCs to TLR9 and Fc epsilon RI alpha receptor expression in allergic and non-allergic subjects. Basophil-depleted mononuclear cell fractions containing pDCs were prepared from peripheral blood of allergic and non-allergic subjects. Intracellular TLR9 and surface Fc epsilon RI alpha expression in blood dendritic cell antigen-2-positive cells were determined by flow cytometry. Activating anti-IgE antibody, anti-Fc epsilon RI alpha antibody, and TLR9 agonist were used to stimulate cell suspensions, with cytokine levels determined by ELISA. No difference in the frequency of pDCs was detected among allergic (n=9) vs. non-allergic (n=11) subjects (P=0.261). While there was also no difference in the baseline expression of TLR9, pDCs from allergic subjects produced sixfold less IFN-alpha when stimulated with CpG (P=0.002). Conversely, there was higher Fc epsilon RI alpha expression (P=0.01) on the pDCs of allergic subjects. Impaired TLR9-dependent immune responses in human pDCs are associated with allergic status and inversely correlated with Fc epsilon RI alpha expression. This impaired innate immune response among dendritic cells of allergic subjects may lead to more targeted therapeutic approaches and could provide a better understanding of the mechanisms underlying conventional and CpG-based immunotherapy.

CpG‐containing immunostimulatory sequences (ISS) exhibit potent inhibition of HCV replication in HCV replicon line

Only 50% of HCV‐infected patients respond to current treatment and many subjects experience adverse effects stemming from systemic IFN‐a administration, underlining the need for safer and more efficacious therapies. Exposure of Huh‐7 replicon cells, an in vitro HCV replication system, to supernatants from human PDCs stimulated with IFN‐a‐inducing CpG‐C ISS also displayed a potent ability to inhibit HCV replication that correlated with the quantity of IFN‐a present in the supernatants. To more closely mimic the in vivo situation, co‐cultures of replicon cells and human PDCs were established. In this case, HCV replication was also inhibited by direct ISS treatment, and optimal inhibition was achieved using lower doses of ISS than were necessary via PDC‐supernatant transfer. Type I IFN blockade during the co‐culture was insufficient to completely inhibit HCV replication, suggesting that other ISS‐induced factors contribute to controlling HCV replication. Furthermore, the dose of efficacious ISS could be further reduced when administered together with the antiviral drug ribavirin, suggesting that effective combination therapy might be achieved with low doses of ISS. These results suggest that a novel combination therapy of ISS and ribavirin could exhibit potent HCV suppressive activity while avoiding adverse events associated with high levels of systemic IFN‐a.

Cutting Edge: Progesterone Regulates IFN-α Production by Plasmacytoid Dendritic Cells

Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman's risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-alpha upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-alpha production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-alpha production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-alpha induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-alpha production by pDCs, Pg may regulate antiviral immunity.

PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation

Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor α and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K δ subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor κB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases.

Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling

Genome-wide expression profiling of mouse and human leukocytes reveal conserved transcriptional programs of plasmacytoid or conventional dendritic cell subsets.