Streptococcus pyogenes activates human plasmacytoid and myeloid dendritic cells

Human peripheral blood contains two major dendritic cell (DC) populations, namely CD11c(-)CD123+ plasmacytoid DCs (PDCs) and CD11c+CD123(-) myeloid DCs (MDCs). Although the activation of these DC types by various TLR ligands has been relatively well-characterized, less is known about the ability of whole live bacteria to induce PDC and MDC activation. In the present report, we have compared the activation of human PDCs and MDCs in response to major human bacterial pathogen Streptococcus pyogenes (group A streptococci) and influenza A virus. S. pyogenes stimulation resulted in the maturation of both DC types, as evidenced by enhanced expression of costimulatory molecules and production of proinflammatory cytokines and chemokines. Furthermore, S. pyogenes-stimulated PDCs and MDCs activated na?ve CD4+ T cells and enhanced their Th1 cytokine production. Influenza A virus infection induced rapid PDC activation, whereas MDCs were extremely sensitive to influenza A virus-induced cell death. The most significant differences between DC types were seen in the production of IL-10 and IL-12, which were only produced by S. pyogenes-stimulated MDCs. Although S. pyogenes was able to induce PDC activation, only influenza A virus infection resulted in detectable IFN-alpha production. Our results show that depending on the infecting microbe, the functions of PDCs and MDCs may be partially overlapping, suggesting a considerable flexibility of the human DC system.     

Prostaglandin E2 is a negative regulator on human plasmacytoid dendritic cells

Prostaglandin E2 (PGE2), a major lipid derived from the metabolism of arachidonic acid, is an environmentally bioactive substance produced by inflammatory processes and acts as a cAMP up-regulator that plays an important role in immune responses. It has been reported that PGE2 has the ability to inhibit the production of interleukin-12 by myeloid dendritic cells (MDCs) and macrophages, and then induce preferential T helper type 2 (Th2) cell responses. However, little is known of the function of PGE2 for plasmacytoid dendritic cells (PDCs), which may contribute to the innate and adaptive immune response to viral infection, allergy and autoimmune diseases. In the present study, we compared the biological effect of PGE2 on human PDCs and MDCs. PGE2 caused the death of PDCs but MDCs survived. Furthermore, we found that, whereas PGE2 inhibited interferon-alpha production by PDCs in response to virus or cytosine-phosphate-guanosine, it inhibited interleukin-12 production by MDCs in response to lipopolysaccharide (LPS) or poly(I:C). Although both virus-stimulated PDCs and LPS-stimulated MDCs preferentially induced the development of interferon-gamma-producing Th1 cells, pretreatment with PGE2 led both DC subsets to attenuate their Th1-inducing capacity. These findings suggest that PGE2 represents a negative regulator on not only MDCs but also PDCs.     

Aberrant composition of the dendritic cell population in hepatic lymph nodes of patients with hepatocellular carcinoma

Patients with hepatocellular carcinoma (HCC) are characterized by a weak T-cell response to their tumor, and chronic carriers of hepatitis B virus or hepatitis C virus have a poor T-cell response against the virus. These inadequate T-cell responses may be due to insufficient activation of the T cells by dendritic cells (DCs). Because lymph nodes (LNs) are the primary site of antigen-specific T-cell activation, we hypothesized that hepatic LNs of patients with HCC and/or chronic viral hepatitis might have aberrant compositions of their DC populations. To address this hypothesis, we enumerated mature myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in hepatic LNs by quantitative immunohistochemistry. Patients with HCC and chronic viral hepatitis and patients with chronic viral hepatitis without HCC were compared with patients with liver inflammation of nonviral etiology and with organ donors with healthy livers. The numbers of PDCs and mature MDCs in hepatic LNs of patients with chronic viral hepatitis did not differ from those of patients with liver inflammation of nonviral etiology nor from individuals with healthy livers. However, hepatic LNs of patients with HBV or HCV infection complicated by HCC showed a 1.5-fold reduction in numbers of mature MDCs and a 4-fold increase in numbers of PDCs in their T-cell areas compared with those of patients with viral hepatitis only (P <.01). In conclusion, patients with HCC have an aberrant composition of the DC population in their hepatic LNs. This may be one of the causes of the inadequate T-cell response against HCC in these patients.     

Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency

Abnormalities in peripheral blood B cell subsets have been identified in common variable immunodeficiency (CVID) patients and classification systems based upon their numbers have been proposed to predict the clinical features. We analysed B lymphocyte subsets by multi-colour flow cytometry (MFC) in a cohort of well-characterized CVID patients to look at their clinical relevance and validate the published association of different classification criteria (Freiburg, Paris and Euroclass) with clinical manifestations. CVID patients had a reduced proportion of total and switched memory B cells (MBC, swMBC) compared to normal controls (P < 0·0006). Patients classified in Freiburg Ia had a higher prevalence of granulomatous diseases (P = 0·0034). The previously published associations with autoimmune diseases could not be confirmed. The Euroclass classification was not predictive of clinical phenotypes. The absolute numbers of all B cell subsets were reduced in CVID patients compared to controls. There was a significant linear correlation between low absolute total B cells and MBC with granulomatous disease (P < 0·05) and a trend towards lower B cells in patients with autoimmune diseases (P = 0·07). Absolute number of different B cell subsets may be more meaningful than their relative percentages in assessing the risk of granulomatous diseases and possibly autoimmunity.     

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

Human Valpha24+ Vbeta11+ natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as alpha-galactosylceramide (alpha-GalCer) presented on CD1d. In the present study we found that highly purified Valpha24+ NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen alpha-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by alpha-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented alpha-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-alpha, whereas full activation of NKT cells as indicated by IFN-gamma production required cell-to-cell contact of PDC and NKT cells in addition to IFN-alpha; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance alpha-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen.     

T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections

Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.     

Active vaccination in patients with common variable immunodeficiency (CVID)

Active vaccination of CVID patients with standard vaccines has rarely been studied in depth although some patients have been shown to develop transient vaccine-specific immunity. We addressed the question whether these patients can be identified by functional classification of their B cell subsets in vitro. Twenty-one CVID patients receiving regular IgG substitution were immunized with anti-peptide and anti-polysaccharide vaccines. Humoral vaccination responses were compared to the numbers of circulating memory B cells, CD21(low) B cells and the capacity to produce antibodies in vitro. Our findings allow four conclusions: (1) positive vaccination responses are not contradictory to the diagnosis of CVID; they occurred against polypeptide vaccines in 23% and against polysaccharide antigens in 18% of all vaccinations. (2) Class-switched antibody responses occur preferentially in patients of CVID group II. (3) A normal percentage of IgM memory B cells is necessary but not sufficient for a vaccination response to polysaccharide antigens. (4) Active vaccination in addition to IgG replacement therapy should be performed in patients of CVID type II - especially in case of vaccines for which passive protection cannot be guaranteed.     

Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry

CVID is frequently diagnosed in male and female individuals with hypogammaglobulinaemia of unknown aetiology. To examine the possibility that sporadic male cases with X-linked agammaglobulinaemia (XLA), which is caused by mutations in the Bruton's tyrosine kinase (Btk) gene, might be misregistered as having CVID, we employed a flow cytometric test to identify XLA in hypogammaglobulinaemic males registered as CVID in the Japanese Immunodeficiency Registry. From 30 male cases registered as having CVID between 1992 and 1998, we selected 21 males with low or unreported peripheral B cell counts. Blood samples could be obtained from 11 patients and their mothers. Using flow cytometric analysis, the Btk-deficient status in monocytes was demonstrated in seven out of nine cases with decreased numbers of peripheral B cells. The diagnosis of XLA was confirmed in each of the seven patients by demonstration of Btk gene mutations in the patients or cellular mosaicism in the mother. This study demonstrates misregistration of XLA as CVID.     

Differential dysfunction in dendritic cell subsets during chronic HCV infection

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with over 200 million individuals infected worldwide. The vast majority of acutely infected humans develop chronic infection, which is characterized by attenuated antiviral T-cell responses. The mechanisms leading to such attenuation/suppression are poorly understood. It has been proposed that dysfunction of antigen-presenting cells (APC) may underlie the downregulation of antiviral immune responses. However, studies using bulk or in vitro-derived APC populations have resulted in conflicting reports. In this study, we evaluated the functional and immunophenotypic features of ex vivo-purified dendritic cell (DC) subsets during chronic HCV infection. We found that plasmacytoid DC (PDC) from HCV-infected patients (HCV-PDC) showed a striking deficit in IFN-alpha production in response to CpG stimulation. In addition, we found that myeloid DC (MDC) from these patients showed a diminished capacity to induce a mixed lymphocyte response (MLR), correlating with lower levels of HLA-DR and CD86 expression and higher IL-10 production in response to poly-IC stimulation. In contrast, HCV-PDC showed increased ability to stimulate an MLR. Of note, within the HCV-PDC preparation, we noted a distinctly expanded DC subset that expressed some markers of MDC, but showed significantly lower HLA-DR and CD86 expression, suggesting an expansion of DC at an immature/intermediate stage of differentiation. Our studies demonstrate distinct and contrasting dysfunctional features in DC subsets and underscore the importance of evaluating APC subpopulations separately.     

Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C

Patients with chronic hepatitis C (CHC) are unable to prime and maintain vigorous T cell responses that are initiated during the acute phase of hepatitis C virus (HCV) infection. As dendritic cells (DCs) induce and regulate both innate and adaptive immune responses, the aim of this study was to analyse two critical functions of DCs: firstly, production of interferon (IFN)-alpha and, secondly, polarization of T helper 1 lymphocytes. The frequencies of plasmacytoid DC (PDC) and myeloid DC (MDC) were estimated in 63 patients with CHC and 34 normal controls using four-colour flow cytometry. Circulating DCs were isolated from peripheral blood of CHC patients (n = 10) and normal controls (n = 10). These DCs were cultured with herpes simplex virus-1 to evaluate their capacity to produce IFN-alpha. The capacity of DCs to induce polarization of autologous naive CD4(+) T lymphocytes to IFN-gamma-producing effector T lymphocytes was also assessed. The frequencies of PDCs producing intracellular IFN-alpha (P < 0.01) and the levels of IFN-alpha in culture supernatant of PDCs (P < 0.01) were significantly lower in patients with CHC compared to those of normal controls. The numbers of MDC were significantly lower in patients with CHC (8.2 (6.0)/ micro l, median (interquartile range), n = 63) compared to normal control (11.7 (7.8)/ micro l, n = 34) (P < 0.01). Moreover, DCs from patients with CHC induced significantly lower numbers of IFN-gamma-producing effector T lymphocytes compared to that of controls (P < 0.01). This study indicates that the low IFN-alpha-producing capacity and impaired T helper 1 polarization ability of DCs from patients with CHC might be responsible for the typical low anti-HCV immune responses in these patients.     

Analysis of plasmacytoid and myeloid dendritic cells in nasal epithelium

The role of plasmacytoid dendritic cells (PDC), the major producers of alpha interferon upon viral infection, in the nasal mucosa is largely unknown. Here we examined the presence of PDC together with myeloid dendritic cells (MDC) in the nasal epithelia of healthy individuals, of asymptomatic patients with chronic nasal allergy, of patients undergoing steroid therapy, and of patients with infectious rhinitis or rhinosinusitis. Considerable numbers of PDC and MDC could be detected in the nasal epithelium. Furthermore, we demonstrate the expression of SDF-1, the major chemoattractant for PDC, in the nasal epithelium. PDC levels were significantly lower for patients with allergies than for healthy individuals. Interestingly, PDC and MDC were almost absent from patients who received treatment with glucocorticoids, while very high numbers of PDC were found for patients with recent upper respiratory tract infections. Our results demonstrate for the first time a quantitative analysis of PDC and MDC in the healthy nasal epithelium and in nasal epithelia from patients with different pathological conditions. With the identification of PDC, the major target cell for CpG DNA or immunostimulatory RNA, in the nasal epithelium, this study forms the basis for a local nasal application of such oligonucleotides for the treatment of viral infection and allergy.     

Deficiency in circulating natural killer (NK) cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia

Absolute and relative NK cell numbers were determined in peripheral whole blood by flow cytometry in patients with common variable immunodeficiency (CVID) (n = 55) and X-linked agammaglobulinaemia (XLA) (n = 19) on regular immunoglobulin (IVIG) therapy. Absolute CD3-CD16+ NK cell numbers were significantly reduced in CVID patients (median 108/microl, range 23-815), compared with normal subjects (n = 60) (289/microl, range 56-640, P < 0.001). Total lymphocyte concentrations were significantly lower in CVID (median 1587/microl, range 523-7519) compared with normal subjects (median 2019/microl, range 1124-3149, P = 0.004), with the percentage of NK cells also being significantly decreased (median 7.5%, range 3.0-33. 0%, compared with 14.2%, range 2.6-30.8%, P < 0.001). In XLA, absolute NK cell numbers (median 140/microl, range 32-551, P < 0. 001) but not relative numbers were significantly reduced compared with normal controls. We excluded the possibility that IVIG interferes with in vitro binding of CD16 MoAbs. Further analysis of NK cell subsets showed a deficiency of both CD16+ and CD56+ cells in CVID, most marked in the CD3-CD8dim subpopulation, which may be due to increased homing of these cells to the gut. Serial studies on a small number of patients suggest that IVIG therapy has no short-term effect on NK cells, although we cannot exclude an effect with prolonged use. Although there are no obvious clinical effects of the NK depletion in CVID and XLA, this may be a factor in their predisposition to cancer.     

Subversion of plasmacytoid and myeloid dendritic cell functions in chronic HCV infection

Insufficient elimination of the hepatitis C virus (HCV) during acute infection results in chronic disease in the majority of patients due to weak virus-specific immune responses. Dendritic cells (DC) play a central role in recognition of HCV and in induction of innate and adaptive immune responses. In this study, we evaluated the frequency and functions of plasmacytoid dendritic cells (PDC) and myeloid dendritic cells (MDC) in patients with chronic HCV infection. We found that both the numbers and IFNalpha production capacity of blood PDC were significantly reduced in patients with chronic HCV infection compared to normal controls. While the frequency of MDC was not affected in chronic HCV, the allostimulatory capacity of monocyte-derived MDC was significantly decreased compared to normals. Lipopolysaccharide (LPS)-induced maturation improved the allostimulatory capacity of HCV infected patients' MDC that still remained significantly lower compared to normal controls. Our experiments revealed that MDC defects can be induced by HCV core and NS3 proteins suggesting virus-induced mechanisms for the DC defects in HCV infection. Finally, using toll-like receptor 2 (TLR2) and TLR4 deficient or mutant mice, we demonstrated that TLR2 but not TLR4 was critical in recognition of HCV core and NS3 proteins by innate immune cells. Further, TLR2 recognition of HCV core and NS3 was not augmented by co-expression of the TLR co-receptor, CD14. These data demonstrate that both PDC and MDC functions are impaired in patients with chronic HCV infection and DC defects are likely related to interaction of HCV viral products with innate immune cells.     

Immunomagnetic selection of functional dendritic cells from human lymph nodes

It was investigated whether positive immunomagnetic selection with two novel DC-specific mAb allowed purification of functional myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC) from the human lymph nodes (LN). The results were compared with enrichment of DC by low-density Nycodenz gradient centrifugation followed by immunomagnetic depletion of residual B- and T-cells (Nycodenz method). MDC were selected from inguinal LN cell suspensions using CD1c mAb and PDC using anti-BDCA-4 mAb. Immunomagnetic selection with anti-CD1c mAb yielded highly pure MDC preparations (90 +/- 3% MDC; n = 7), provided that the B-cells were thoroughly depleted by using CD19 magnetic beads and Large Depletion (LD) columns prior to selection of MDC. The purified MDC comprised both mature and immature cells and were functional, secreting large amounts of cytokines upon stimulation and strongly stimulating allogeneic T-cell proliferation. Immunomagnetic selection with anti-BDCA-4 mAb enriched PDC 70-fold to a purity of 59 +/- 26% (n = 8). The contamination consisted mainly of BDCA-4(+) T- and NK-cells. The previously used Nycodenz method yielded mixtures of MDC and PDC, not allowing functional studies of MDC and PDC separately. In conclusion, positive immunomagnetic selection with CD1c mAb from human LN cell suspensions yields almost pure MDC preparations, which are, in contrast to those obtained by the Nycodenz method, not contaminated with PDC. Moreover, these MDC are functionally intact. Selection with anti-BDCA-4 mAb does enrich PDC from human LN, but the resulting preparations are contaminated with T- and NK-cells.     

Decreased blood dendritic cell counts in type 1 diabetic children

In this study DC numbers, phenotype and DC responses to the Toll-like receptor (TLR)-3 ligand, poly I:C, were examined in new-onset Type 1 diabetes (T1D) patients (ND) and in established T1D patients (ED). Absolute blood myeloid DC (MDC) and plasmacytoid DC (PDC) numbers were decreased in ND and ED patients compared to age-matched controls. The decrease in MDC and PDC counts was less evident in patients with a combination of T1D and coeliac disease (CD) or CD alone. The age-dependent decline in blood DC numbers, found in control children, was not evident in ND patients, such that 2-10 years old ND children had similar MDC and PDC numbers to 15-17 years old controls. In ED patients the t-score of MDC and PDC numbers related to the age of diagnosis but not to disease duration. Blood DC in T1D patients were not distinguished from those of controls by the levels of HLA-DR, CD40 and CD86 expression or the percentage of DC expressing cytokines, IL-12, IL-10, IL-6 and TNF-alpha, in responses to poly I:C. If low DC numbers are shown to contribute to the autoimmunity in T1D, interventions aimed to increase DC numbers may mitigate against beta-cell loss.     

粒细胞集落刺激因子诱导的供者外周血中两种不同亚群树突状细胞免疫生物学特性的研究

目的 从粒细胞集落刺激因子(G-CSF)诱导的供者外周血中分离出CD1c+的髓细胞性DC(MDC)、CD304+类浆细胞样DC(PDC)两类DC亚群,并对其生物学特性进行分析和研究.方法 免疫磁珠法分离出MDC、PDC,分别用TNF-α、CpG2006OND诱导成熟,检测各DC亚群的表型、对同种异基因淋巴细胞的刺激反应.结果 分选的DC纯度均＞95%,MDC表达HLA-DR、CD11c、CD33、CD4,PDC表达HLA-DR、CD4、CD45RA,诱导成熟的两类DC的CD40、CD80表达均明显增高;混合淋巴细胞反应(MLR)显示:MDC具有很强的刺激淋巴细胞增殖能力,PDC刺激能力很弱;各组上清液中IFN-r均增加,MDC、mMDC组增高最为明显;PDC、mPDC刺激组上清液中IL-10明显增高;MDC、mMDC刺激后,胞浆内表达IFN-r的CD4+T细胞均明显增高;PDC、mPDC有上调CIM+CD25high调节性T细胞(Treg)作用;Foxp3 mRNA的表达在各组间无明显的差异.结论 采集的供者外周血中两类DC亚群虽然HLA-DR高表达,但仍处于非成熟状态,在合适的条件下分化成熟;无论MDC成熟与否均表现出很强的刺激T细胞增殖能力,使T细胞分泌IFN-r增加,其分泌的增加可能是促进向TH1极化的结果.PDC可能并不像MDC一样有效地捕获、处理和负载抗原到MHC分子上,因此提呈抗原效率低,表现出对T细胞的弱刺激增殖特性;PDC虽然也可以促进T细胞分泌IFN-r,但似乎并非是通过TH1细胞;PDC并不能促进TH2类因子IL-4的分泌,对TH2的极化作用可能表现在IL-10的分泌上;PDC有诱导CD4+CD25highTreg的作用.     

Reciprocal regulation of plasmacytoid dendritic cells and monocytes during viral infection.

Reciprocal regulation of opposing functions characterizes biological systems. We now show that adenovirus-infected plasmacytoid dendritic cells (PDC) inhibit monocyte to myeloid dendritic cell (MDC) differentiation and function, and that adenovirus-infected monocytes inhibit PDC type I interferon secretion. Adenovirus-infected PDC secreted IFN-alpha, beta and omega in an 86:2:1 ratio. PDC type I interferons inhibited MDC differentiation and function (reduced IL-12 secretion, IFN-gamma induction, MLR and CD40 expression, and increased CD1a(+)CD14(+) cells). Type I interferon receptor blocking antibody reversed all PDC effects, and recombinant IFN-alpha, beta or omega replicated all effects, except reduced CD40. Adenovirus-infected monocytes suppressed PDC type I interferon secretion, which was reversed with anti-IL-10 neutralizing antibodies. Exogenous IL-10 suppressed PDC type I interferon secretion without reducing PDC viability. Therefore, monocyte IL-10 regulates PDC type I interferon secretion, and PDC type I interferons inhibit MDC differentiation and function. Such reciprocal regulation of potentially opposing influences may help modulate anti-pathogen immunity.     

Plasmacytoid dendritic cells induce a distinct cytokine pattern in virus-specific CD4+ memory T cells that is modulated by CpG oligodeoxynucleotides

Inherent properties of dendritic cell (DC) subsets are important in the regulation of naïve T‐cell differentiation (e.g. Th1 versus Th2 cells), whereas effector memory T cells are believed to produce a fixed cytokine repertoire independent of the type of antigen presenting cell. Here we show that two distinct human DC subsets, plasmacytoid DC (PDC) and myeloid CD11c+ DC, induced autologous mumps virus‐specific memory CD4⁺ T cells to produce markedly different cytokine patterns upon antigen stimulation. PDC stimulated the T cells to produce γ‐interferon (IFN‐γ) and interleukin‐(IL)‐10, whereas CD11c+ DC induced lower levels of IFN‐γ, virtually no IL‐10, but significant levels of IL‐5. Analysis of intracellular cytokine production showed simultaneous production of IL‐10 and IFN‐γ in mumps‐specific T cells activated by PDC, a cytokine pattern similar to that described for Th1‐like regulatory cells. Introduction of CpG oligodeoxynucleotides in PDC/T‐cell co‐cultures had synergistic effect on virus‐dependent IFN‐γ production, whereas the other cytokines remained unchanged. Together, our results show that the type of DC involved in reactivation of previously primed T cells may have significant impact on the resulting cytokine response and suggest that targeting of viral antigens and adjuvant to specific DC subsets should be considered in the design of therapeutic antiviral vaccines.     

Memory B cells in common variable immunodeficiency: clinical associations and sex differences

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff 相似文献