Function Of Plasmacytoid Dendritic Cells Research Articles

Regulation on function and maturation of plasmacytoid dendritic cells by triptolide

Objective To explore the mechanism of immunomodulatory activity of triptolide on healthy volunteers peripheral blood mononuclear cells （PBMC）-derived plasmacytoid dendritic cells （pDCs）. Methods Healthy volunteers-derived pDCs were sorted by flow cytometry, then incubated with triptolide （0, 5, 10, 30 μg/L）. After 24 hours, we detected the concentration of IFN-α, IL-6, TNF-α using ELISA. After 5 days, the cultrural cells were collected and analyzed by flow cytometry, light microscope and electron microscope scanning. Results Triptolide-treated pDCs secreted lower level of IFN-α,IL-6 ,TNF-α, triptolide could inhibit pDCs differentiation to DCs which displayed more immature morphology and immunophenotypes than untreated-pDCs. Conclusion Triptolide could decrease the immune function of pDCs, inhibit differentiation and maturation of pDCs. Key words: Triptolide ; Plasmacytoid dendritic cells ; Maturation

Interleukin-2 inhibits FMS-like tyrosine kinase 3 receptor ligand (flt3L)-dependent development and function of conventional and plasmacytoid dendritic cells

Steady-state development of plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known about how other cytokines may also control this process. In this study, we show that IL-2 inhibits the development of both pDCs and cDCs from bone marrow cells under flt3L stimulation, by acting on lineage(-) flt3(+) precursors. This inhibition of DC development by IL-2 requires IL-2Rα and IL2Rβ. IL-2Rα is specifically expressed in one stage of the DC precursor: the monocyte and DC progenitors (MDPs). Furthermore, more MDPs are found in flt3L-stimulated bone marrow cultures when IL-2 is present, suggesting that IL-2 may be inhibiting DC development at the MDP stage. Consistent with our in vitro findings, we observe that nonobese diabetic (NOD) mice, which express less IL-2 compared with diabetes-resistant NOD.Idd3/5 mice, have more splenic pDCs. Additionally, DCs developed in vitro in the presence of flt3L and IL-2 display reduced ability to stimulate T-cell proliferation compared with DCs developed in the presence of flt3L alone. Although the addition of IL-2 does not increase the apoptosis of DCs during their development, DCs developed in the presence of IL-2 are more prone to apoptosis upon interaction with T cells. Together our data show that IL-2 can inhibit both the development and the function of DCs. This pathway may have implications for the loss of immune tolerance: Reduced IL-2 signaling may lead to increased DC number and T-cell stimulatory capacity.

Decreased numbers of peripheral blood dendritic cells in patients with coronary artery disease are associated with diminished plasma Flt3 ligand levels and impaired plasmacytoid dendritic cell function

We investigated whether activation of circulating DCs (dendritic cells) or levels of Flt3L (FMS-like tyrosine kinase 3 ligand) and GM-CSF (granulocyte/macrophage colony-stimulating factor), haematopoietic growth factors important for DC differentiation, could account for reduced blood DC numbers in CAD (coronary artery disease) patients. Concentrations of Flt3L and GM-CSF were measured in plasma from CAD patients (n = 15) and controls (n = 12). Frequency and phenotype of mDCs (myeloid dendritic cells) and pDCs (plasmacytoid dendritic cells) were analysed by multicolour flow cytometry in fresh blood, and after overnight incubation with TLR (Toll-like receptor)-4 or -7 ligands LPS (lipopolysaccharide) or IQ (imiquimod). DC function was measured by IL (interleukin)-12 and IFN (interferon)-α secretion. Circulating numbers of CD11c+ mDCs and CD123+ pDCs and frequencies of CD86+ and CCR-7+ (CC chemokine receptor type7) mDCs, but not pDCs, were declined in CAD. In addition, plasma Flt3L, but not GM-CSF, was lower in patients and positively correlated with blood DC counts. In response to LPS, mDCs up-regulated CD83 and CD86, but CCR-7 expression and IL-12 secretion remained unchanged, similarly in patients and controls. Conversely, pDCs from patients had lower CD83 and CCR-7 expression after overnight incubation and had a weaker IQ-induced up-regulation of CD83 and IFN-α secretion. In conclusion, our results suggest that reduced blood DC counts in CAD are, at least partly, due to impaired DC differentiation from bone marrow progenitors. Decreased levels of mDCs are presumably also explained by activation and subsequent migration to atherosclerotic plaques or lymph nodes. Although mDCs are functioning normally, pDCs from patients appeared to be both numerically and functionally impaired.

Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis

AbstractDendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs.

Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity

Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly.

Molecular mechanisms for plasmacytoid dendritic cell function and development

Dendritic cells (DCs) are activated by immune adjuvants in a DC subset-specific manner. Plasmacytoid DC (pDC) is a unique subset that senses nucleic acid immune adjuvants only through two Toll-like receptors (TLRs), TLR7 and TLR9 and produces large amounts of type I interferons. Here I review recent trend in pDC function and development.

A Systems Immunology Approach to Plasmacytoid Dendritic Cell Function in Cytopathic Virus Infections

Plasmacytoid dendritic cell (pDC)-mediated protection against cytopathic virus infection involves various molecular, cellular, tissue-scale, and organism-scale events. In order to better understand such multiscale interactions, we have implemented a systems immunology approach focusing on the analysis of the structure, dynamics and operating principles of virus-host interactions which constrain the initial spread of the pathogen. Using high-resolution experimental data sets coming from the well-described mouse hepatitis virus (MHV) model, we first calibrated basic modules including MHV infection of its primary target cells, i.e. pDCs and macrophages (Mφs). These basic building blocks were used to generate and validate an integrative mathematical model for in vivo infection dynamics. Parameter estimation for the system indicated that on a per capita basis, one infected pDC secretes sufficient type I IFN to protect 103 to 104 Mφs from cytopathic viral infection. This extremely high protective capacity of pDCs secures the spleen's capability to function as a ‘sink’ for the virus produced in peripheral organs such as the liver. Furthermore, our results suggest that the pDC population in spleen ensures a robust protection against virus variants which substantially down-modulate IFN secretion. However, the ability of pDCs to protect against severe disease caused by virus variants exhibiting an enhanced liver tropism and higher replication rates appears to be rather limited. Taken together, this systems immunology analysis suggests that antiviral therapy against cytopathic viruses should primarily limit viral replication within peripheral target organs.

Myeloid and plasmacytoid dendritic cells in induced sputum after allergen inhalation in subjects with asthma

Dendritic cells are professional antigen presenting cells that mediate the response to inhaled allergens. In animal models, the induction and maintenance of allergic airway inflammation is primarily a function of myeloid dendritic cells, whereas the tolerization to inhaled allergens is likely a function of plasmacytoid dendritic cells. To investigate changes in sputum myeloid and plasmacytoid dendritic cells after allergen inhalation in subjects with asthma. Also, the number of myeloid and plasmacytoid dendritic cells expressing both CCR6 and 7 and their chemokine ligands macrophage inflammatory protein (MIP)-3alpha and 3beta were measured in sputum supernatants. Sputum was induced from 12 dual-responder subjects with allergic asthma before and 7 hours, 24 hours, and 72 hours after inhalation of diluent and allergen. Dendritic cells were enumerated via flow cytometry and the chemokines by using ELISAs. The number of sputum myeloid dendritic cells was significantly higher 24 hours after allergen challenge compared with diluent. Similarly, sputum plasmacytoid dendritic cells increased significantly at 24 hours after allergen challenge. Also, a significant increase in CCR6(+) myeloid dendritic cells numbers occurred 72 hours after allergen challenge. In contrast, CCR7(+) myeloid dendritic cells, as well as the number of CCR6(+) and CCR7(+) plasmacytoid dendritic cells, were not different between challenges. Finally, allergen challenge increased sputum levels of MIP-3alpha, but not MIP-3beta, compared with baseline. Both myeloid and plasmacytoid dendritic cells increase in the sputum of subjects with asthma after allergen challenge, suggesting that both subsets are involved in the pathogenesis of allergen responses in asthma.

Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance.

Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCs and type I IFN responses mainly through the Toll-like receptor pathway. However, a variety of activating and inhibitory pDC receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCs promote immunity and autoimmunity, resting or alternatively activated pDCs may be tolerogenic. The various roles of pDCs have been extensively studied in vitro and in vivo with depleting antibodies. However, depleting antibodies cross-react with other cell types that are critical for eliciting protective immunity, potentially yielding ambiguous phenotypes. Here we discuss new approaches to assess pDC functions in vivo and provide preliminary data on their potential roles during viral infections. Such approaches would also prove useful in the more specific evaluation of how pDCs mediate tolerance and autoimmunity. Finally, we discuss the emergent role of pDCs and one of their receptors, tetherin, in human immunodeficiency virus pathogenesis.

Loss of Plasmacytoid Dendritic Cell Function Coincides with Lymphopenia and Viremia During Foot-and-Mouth Disease Virus Infection

Foot-and-mouth disease virus (FMDV) causes an acute, highly contagious disease of livestock. Though FMDV is very sensitive to interferon-alpha (IFN-alpha), IFN-beta, and IFN-gamma, the virus has evolved mechanisms to evade such innate responses. For instance, during acute infection, FMDV suppresses IFN-alpha production by skin and myeloid dendritic cells (DCs). We have previously reported that FMDV infection induces a transient lymphopenia and interruption of T-lymphocyte responses to mitogenic stimuli. To further understand the immunopathogenesis of FMD, we have now analyzed the serum IFN-alpha response in relation to lymphopenia, and the number and function of plasmacytoid DCs (pDCs) following infection of pigs with multiple serotypes of FMDV. Serum IFN-alpha peaked 2-3 d post-infection (PI), regardless of FMDV serotype. Lymphopenia coincided with peak viremia and the serum IFN-alpha response. Circulating pDC numbers and in-vitro pDC IFN-alpha secretion transiently declined by 48 h following infection. Infection of lymphocytes or pDCs was never detected regardless of the FMDV serotype inoculated or the age of the animal infected. These data indicate that, like other DC subsets, there is suppression of interferon production by pDCs, which abrogates this important innate response. Rapid induction of serum IFN-alpha, albeit short-lived, may contribute to the rapid resolution of FMDV viremia prior to induction of specific immunity.

Differential Effects of P-Class Versus Other CpG Oligodeoxynucleotide Classes on the Impaired Innate Immunity of Plasmacytoid Dendritic Cells in HIV Type 1 Infection

Abstract Human plasmacytoid dendritic cells (PDC) are the major producers of type I interferons (IFN) after stimulation with CpG oligodeoxynucleotides (ODN). HIV-1-infected patients show a deficit in PDC numbers and function with progression of disease. CpG ODN appear to be attractive therapeutics to support the impaired innate immunity in HIV-1 infection. PDC counts, phenotype, and function were analyzed in 23 HIV-infected untreated individuals and 16 controls. Markers for migration (CCR7), activation (CD80), maturation (CD83), and endocytosis (BDCA2) were evaluated at baseline and 20 h after in vitro stimulation with class A, B, C, and P ODN. PDC counts and the expression of BDCA2 on these cells were significantly lower in HIV-1-infected subjects compared to controls (both p < 0.001). After stimulation with CpG ODN, CD80 and CD83 were upregulated to a similar extent in patients and controls, whereas CCR7 was upregulated more efficiently by CpG-P and CpG-C than CpG-A in HIV-1-infected individuals compared to controls. The IFN-alpha induction significantly differed for the CpG ODN classes (A > P > C > B) in patients and controls (p < 0.05). Functional PDC deficits in IFN-alpha and TNF-alpha induction were particularly evident in subjects with less than 500 CD4(+) cells/mul. CpG-P ODNs not only induced remarkable IFN-alpha production in patient PBMCs, but also significantly upregulated the antibacterial and antiviral CXC chemokine IP-10. In conclusion, PDC counts, phenotype, and function are significantly impaired in HIV-1-infected subjects. Optimized P-class ODN may be effective in reversing this innate immune defect, which should be further evaluated in vivo.

Co-ordinated regulation of plasmacytoid dendritic cell surface receptors upon stimulation with herpes simplex virus type 1.

Human plasmacytoid dendritic cells (PDC) are crucial for innate and adaptive immune responses against viral infections, mainly through production of type I interferons. Evidence is accumulating that PDC surface receptors play an important role in this process. To investigate the PDC phenotype in more detail, a chip-based expression analysis of surface receptors was combined with respective flow cytometry data obtained from fresh PDC, PDC exposed to interleukin-3 (IL-3) and/or herpes simplex virus type 1 (HSV-1). CD156b, CD229, CD305 and CD319 were newly identified on the surface of PDC, and CD180 was identified as a new intracellular antigen. After correction for multiple comparisons, a total of 33 receptors were found to be significantly regulated upon exposure to IL-3, HSV-1 or IL-3 and HSV-1. These were receptors involved in chemotaxis, antigen uptake, activation and maturation, migration, apoptosis, cytotoxicity and costimulation. Infectious and ultraviolet-inactivated HSV-1 did not differentially affect surface receptor regulation, consistent with the lack of productive virus infection in PDC, which was confirmed by HSV-1 real-time polymerase chain reaction and experiments involving autofluorescing HSV-1 particles. Viral entry was mediated at least in part by endocytosis. Time-course experiments provided evidence of a co-ordinated regulation of PDC surface markers, which play a specific role in different aspects of PDC function such as attraction to inflamed tissue, antigen recognition and subsequent migration to secondary lymphatic tissue. This knowledge can be used to investigate PDC surface receptor functions in interactions with other cells of the innate and adaptive immune system, particularly natural killer cells and cytotoxic T lymphocytes.

Inability of Plasmacytoid Dendritic Cells To Directly Lyse HIV-Infected Autologous CD4 + T Cells despite Induction of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

The function of plasmacytoid dendritic cells (PDC) in chronic human immunodeficiency virus type 1 (HIV-1) infection remains controversial with regard to its potential for sustained alpha interferon (IFN-alpha) production and induction of PDC-dependent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity of HIV-infected cells. We address these areas by a study of chronically HIV-1-infected subjects followed through antiretroviral therapy (ART) interruption and by testing PDC cytolytic function against autologous HIV-infected CD4(+) T cells. Rebound in viremia induced by therapy interruption showed a positive association between TRAIL and viral load or T-cell activation, but comparable levels of plasma IFN-alpha/beta were found in viremic ART-treated and control subjects. While PDC from HIV-infected subjects expressed less interferon regulator factor 7 (IRF-7) and produced significantly less IFN-alpha upon Toll-like receptor 7/9 (TLR7/9) engagement than controls, membrane TRAIL expression in PDC from HIV(+) subjects was increased. Moreover, no significant increase in death receptor 5 (DR5) expression was seen in CD4(+) T cells from viremic HIV(+) subjects compared to controls or following in vitro infection/exposure to infectious and noninfectious virus or exogenous IFN-alpha, respectively. Although activated PDC killed the DR5-expressing HIV-infected Sup-T1 cell line, PDC did not lyse primary autologous HIV(+) CD4(+) T cells yet could provide accessory help for NK cells in killing HIV-infected autologous CD4(+) T cells. Taken together, our data show a lack of sustained high levels of soluble IFN-alpha in chronic HIV-1 infection in vivo and document a lack of direct PDC cytolytic activity against autologous infected or uninfected CD4(+) T cells.

17β-Estradiol Enhances the Response of Plasmacytoid Dendritic Cell to CpG

Gender differences in immune capabilities suggest that sex hormones such as estrogens were involved in the regulation of the immunocompetence. Numerous studies also suggest that plasmacytoid dendritic cells (PDCs) play a pathogenic role in SLE. However, it is unclear whether estrogen can modulate the function of PDCs to influence the development of SLE. In the present study, PDCs from murine spleens were treated with 17β-estradiol (E2) and CpG respectively or both in vitro, then cell viability, costimulatory molecule expression, cytokine secretion of PDCs, as well as stimulatory capacity of PDCs to B cells were analyzed. Results showed that E2 and CpG increased the cell viability and costimulatory molecule expression on PDCs synergistically. Moreover, the intracellular and extracellular secretion of IFN-α was increased by E2 or E2 plus CpG. In addition, E2 and CpG also increased the stimulatory capacity of PDCs to B cells, and the viability of B cells was decreased after neutralizing IFN-α significantly. In the experiments in vivo, mice received daily s.c. injections of E2 and CpG respectively or both, then we found that the plasma concentration of IgM were elevated by E2 and CpG synergistically and the expression of IFN-α/β in spleens were noticeably increased by CpG plus E2 compared with the treatment of E2 or CpG only. This study indicates that E2 could exacerbate PDCs' activation with CpG, which further activates B cells to upregulate susceptibility to autoantigens. IFN-α plays an important role in the stimulatory effect of PDCs on B cells. E2 stimulation of IFN-α production may result in female prevalence in autoimmune diseases such as SLE through activation of PDCs. This study provides novel evidence of relationship between estrogen and SLE and also sheds light on gender biases among SLE patients.

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.

Plasmacytoid dendritic cells accumulate in spleens from chronically HIV-infected patients but barely participate in interferon-α expression

AbstractWe characterized the localization, phenotype, and some functions of plasmacytoid dendritic cells (pDCs) in the human spleen. pDCs were localized in the marginal zone and the periarteriolar region. Some were also found in the red pulp. pDCs were immature by phenotypic labeling, consistently with their capacity to internalize Dextran in a functional assay. In spleens from HIV-infected patients with thrombocytopenic purpura, these characteristics were unaffected. However, an accumulation of pDCs, but not myeloid dendritic cells (mDCs), was observed in some HIV+ patients, correlating with high proviral loads. Moreover, although undetectable in most HIV− patients, interferon-α (IFN-α) production was evidenced in situ and by flow cytometry in most HIV+ patients. IFN-α was located in the marginal zone. Surprisingly, IFN-α colocalized only with few pDCs, but rather with other cells, including T and B lymphocytes, mDCs, and macrophages. Therefore, pDCs accumulated in spleens from HIV+ patients with high proviral loads, but they did not seem to be the main IFN-α producers.

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

Dendritic cells: Transcriptional control of plasmacytoid dendritic cell development by E2‐2

Dendritic cells: Transcriptional control of plasmacytoid dendritic cell development by E2-2

Aberrant function of peripheral blood myeloid and plasmacytoid dendritic cells in atopic dermatitis patients

Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined by the level of production of particular cytokines. Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an initial phase predominated by T(H)2 cytokines that switches into a second, more chronic T(H)1-dominated eczematous phase. To assess to what extent the AD phenotype is associated with an aberrant phenotype and function of DCs. Classic CD1c(+)/blood DC antigen (BDCA)-1(+) myeloid (m) DCs and CD304(+)/BDCA4(+) plasmacytoid (p) DCs, the natural IFN-producing cells, were isolated from peripheral blood of patients with AD and healthy controls and analyzed for their phenotype and function. Purified CD1c(+)/BDCA1(+) mDCs from patients with AD showed a selective and dramatic reduction of IL-12p70 and TNF-alpha release. IL-12p70 reduction was attributed to a defective expression of both IL-12p35 and IL-12p40 subunits. Accordingly, mature CD1c(+)/BDCA1(+) mDCs from patients with AD induced considerably less IFN-gamma-producing and more IL-4-producing T(H) cells compared with mDCs from healthy controls. In addition, CD304(+)/BDCA4(+) pDCs from patients with AD produced significantly lower levels of IFN-alpha compared with healthy controls. Myeloid DCs and pDCs from patients with AD show defective IL-12, TNF-alpha, and IFN-alpha production, which may contribute to increased susceptibility to infection and to the maintenance of the T(H)2 cell-mediated allergic state in patients with AD.

Transcription Factor E2-2 Is an Essential and Specific Regulator of Plasmacytoid Dendritic Cell Development

Plasmacytoid dendritic cells (PDCs) represent a unique immune cell type specialized in type I interferon (IFN) secretion in response to viral nucleic acids. The molecular control of PDC lineage specification has been poorly understood. We report that basic helix-loop-helix transcription factor (E protein) E2-2/Tcf4 is preferentially expressed in murine and human PDCs. Constitutive or inducible deletion of murine E2-2 blocked the development of PDCs but not of other lineages and abolished IFN response to unmethylated DNA. Moreover, E2-2 haploinsufficiency in mice and in human Pitt-Hopkins syndrome patients was associated with aberrant expression profile and impaired IFN response of the PDC. E2-2 directly activated multiple PDC-enriched genes, including transcription factors involved in PDC development (SpiB, Irf8) and function (Irf7). These results identify E2-2 as a specific transcriptional regulator of the PDC lineage in mice and humans and reveal a key function of E proteins in the innate immune system.