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DC Subsets (dc + subset)
Selected AbstractsCD8,+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumorEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Alison M. McDonnell Abstract One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cell-associated tumor antigens to CD8+ T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c+ DC. Further analysis revealed that both CD8,+ and CD8,, DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8,, DC subset. Therefore LN resident CD8,+ DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses. [source] CD40L-expressing CD8 T cells prime CD8,+ DC for IL-12p70 productionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Loon Wong Abstract CD8,+ DC are implicated as the principle DC subset for cross-presentation and cross-priming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8,+ DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8,+ DC, but not CD8,, DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-, and CD40L, which is rapidly up-regulated post-stimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8,+ DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. [source] Mediastinal lymph node CD8,, DC initiate antigen presentation following intranasal coadministration of ,-GalCerEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2007Sung-Youl Ko Abstract Our previous study revealed that ,-galactosylceramide (,-GalCer) is a potent nasal vaccine adjuvant inducing both potent humoral and cellular immune responses and affording complete protection against viral infections and tumors. However, the antigen-presenting cells (APC) that are activated by NKT cells and thereby initiate the immune responses following intranasal coadministration of protein antigen and ,-GalCer are poorly understood. We assessed here where antigen presentation occurs and which APC subset mediates the early stages of immune responses when protein antigen and ,-GalCer are intranasally administered. We show that dendritic cells (DC), but not B cells, initiated the mucosal immune responses at mediastinal lymph nodes. Of the DC subsets, the CD8,,B220,CD11c+ DC subset played the most prominent role in the direct and cross-presentation of protein antigen to naive T cells and in triggering the naive T cells to differentiate into effector T cells. This might be mainly caused by a relatively larger population of CD1dhigh cells of CD8,,B220,CD11c+ DC subset than those of other DC subsets. These results indicate that CD8,,B220,CD11c+ DC is the principal subset becoming immunogenic after interaction with NKT cells and abrogating tolerance to intranasally administered protein antigen when ,-GalCer is coadministered as a nasal vaccine adjuvant. [source] Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005Ingrid Abstract Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. [source] The CD8+ dendritic cell subsetIMMUNOLOGICAL REVIEWS, Issue 1 2010Ken Shortman Summary:, Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8, together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll-like receptor and C-type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8+ DCs are non-migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8, DC neighbors. They efficiently cross-present exogenous cell-bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin-12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self-tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8+ T-cell responses to the invading pathogens. Targeting vaccine antigens to the CD8+ DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses. [source] CD1a expression defines an interleukin-12 producing population of human dendritic cellsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009M. Cernadas Summary Human and murine dendritic cell (DC) subsets are often defined by phenotypic features that predict their functional characteristics. In humans and mice, DC have been shown to have the ability to polarize naive CD4 T cells to a T helper type 1 (Th1) or Th2 phenotype. However, human myeloid DC generated from monocytes (monocyte-derived DC) have often been regarded as a homogeneous population, both phenotypically and functionally. Monocytes give rise to subpopulations of DC in vitro that can be separated on the basis of their expression of CD1a, a well-described DC subset marker. Importantly, we show that the CD1a+ DC subset produces significant quantities of interleukin-12p70 (IL-12p70) upon stimulation and, similar to the murine CD8,+ DC subset, can polarize naive CD4+ T cells to a Th1 phenotype. In contrast, CD1a, DC, similar to murine CD8,, DC, do not produce significant amounts of IL-12p70 upon stimulation or polarize T cells to a Th1 phenotype. Like monocyte-derived DC, CD1a+ and CD1a, DC subsets obtained from CD34+ haematopoietic progenitors under distinct culture conditions were found to have these same features, suggesting that CD1a expression is a marker for myeloid DC that are a major source of IL-12 and Th1 CD4+ T cell polarization in man. [source] CD8,+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumorEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Alison M. McDonnell Abstract One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cell-associated tumor antigens to CD8+ T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c+ DC. Further analysis revealed that both CD8,+ and CD8,, DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8,, DC subset. Therefore LN resident CD8,+ DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses. [source] Strategies for optimizing targeting and delivery of mucosal HIV vaccinesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Jeffrey D. Ahlers Abstract Effective frontline defenses against HIV-1 will require targeting vaccines to mucosal tissue in order to induce ,, CD8+ lymphocytes in mucosal effector sites (lamina propria and intraepithelial compartment) as well as antibody secreting plasma cells that can neutralize and limit free virus. A concerted second wave of assault against the virus will require the activation and recruitment of antigen specific memory CD4+ and CD8+ T cells in mesenteric lymph nodes and distal secondary lymphoid organs. New delivery strategies targeting the "right" DC subsets in combination with delivery of mucosal adjuvants and innate signals for activating DC will be essential for mucosal vaccines in order to circumvent the naturally tolerogenic environment and the induction of Tregs. Mucosal delivery of antigen in combination with inflammatory signals has been shown to empower systemic immunization by directing responses to mucosal sites for imprinting optimum mucosal memory. Here, we discuss novel vaccine strategies and adjuvants for optimizing mucosal delivery of HIV vaccines. [source] Induction of peripheral CD4+ T-cell tolerance and CD8+ T-cell cross-tolerance by dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Manfred B. Lutz Abstract DC can present and cross-present self-antigens to autoreactive CD4+ and CD8+ T cells, respectively, and incapacitate them by inducing anergy, deletion or converting them into Treg. In this review, we summarize the recent progress in immune tolerance research, which has been achieved by employing antigen- and TCR-transgenic mice. We cover the numerous discoveries that have furthered our knowledge of the DC subsets and maturation pathways involved in tolerance; the signals, such as CD70, TGF-,, B7-H1/PD-L1, which dictate the decision between immunity and tolerance; and the in vivo role of DC in the maintenance of CD4+ T-cell tolerance and CD8+ T-cell cross-tolerance. [source] E-box protein E2-2 is a crucial regulator of plasmacytoid DC development,EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2008Eiji Esashi Abstract DC play central roles in priming both innate and adaptive immune responses. Multiple DC subsets have been identified on the basis of their phenotype and function. Plasmacytoid DC (pDC) are professional IFN-producing cells that play an essential role in anti-viral immunity. A series of recent studies demonstrates that the regulation of pDC development is different from other types of DC. In this issue of the European Journal of Immunology, new insight is provided into how human pDC development is regulated by various transcription factors, in particular by the Ets family protein Spi-B and E-box protein E2-2. [source] Mediastinal lymph node CD8,, DC initiate antigen presentation following intranasal coadministration of ,-GalCerEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2007Sung-Youl Ko Abstract Our previous study revealed that ,-galactosylceramide (,-GalCer) is a potent nasal vaccine adjuvant inducing both potent humoral and cellular immune responses and affording complete protection against viral infections and tumors. However, the antigen-presenting cells (APC) that are activated by NKT cells and thereby initiate the immune responses following intranasal coadministration of protein antigen and ,-GalCer are poorly understood. We assessed here where antigen presentation occurs and which APC subset mediates the early stages of immune responses when protein antigen and ,-GalCer are intranasally administered. We show that dendritic cells (DC), but not B cells, initiated the mucosal immune responses at mediastinal lymph nodes. Of the DC subsets, the CD8,,B220,CD11c+ DC subset played the most prominent role in the direct and cross-presentation of protein antigen to naive T cells and in triggering the naive T cells to differentiate into effector T cells. This might be mainly caused by a relatively larger population of CD1dhigh cells of CD8,,B220,CD11c+ DC subset than those of other DC subsets. These results indicate that CD8,,B220,CD11c+ DC is the principal subset becoming immunogenic after interaction with NKT cells and abrogating tolerance to intranasally administered protein antigen when ,-GalCer is coadministered as a nasal vaccine adjuvant. [source] CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Anja Marschner Abstract Human V,24+ V,11+ natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as ,-galactosylceramide (,-GalCer) presented on CD1d. In the present study we found that highly purified V,24+ 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 ,-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 ,-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented ,-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-,, whereas full activation of NKT cells as indicated by IFN,, production required cell-to-cell contact of PDC and NKT cells in addition to IFN-,; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance ,-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. [source] Site-specific expression of CD11b and SIRP, (CD172a) on dendritic cells: implications for their migration patterns in the gut immune systemEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Diane Bimczok Abstract Dendritic cells (DC) in the intestinal tract play a major role in directing the mucosal immune system towards tolerance or immunity. We analyzed whether different mucosal DC subsets in pigs have specific functions, localizations, or migration patterns in vivo. Therefore, we collected physiologically migrating DC by pseudo-afferent cannulation of the intestinal duct in eight Göttingen minipigs. Lymph DC were phenotypically and functionally characterized and compared to DC found on histological sections of porcine small intestine and mesenteric lymph nodes (MLN). Four different DC subpopulations were detected. Lamina propria (LP) DC were mainly CD11b+ signal regulatory protein,, (SIRP,)+, DC in Peyer's patches were mainly CD11b,/SIRP,+ in subepithelial domes and CD11b,/SIRP,, in interfollicular regions, whereas MLN DC were largely CD11b+/SIRP,,. Of these four subsets, only the CD11b+/SIRP,+ DC and the CD11b+/SIRP,, DC were present in lymph. This suggests that DC migration to MLN largely originates from the LP. Lymph DC expressed high levels of MHC class,II and costimulatory molecules and had a low capacity for FITC-dextran uptake, indicating a mature phenotype. However, lymph DC did not induce PBMC proliferation in MLR, and migration was not significantly influenced by mucosal antigen application. [source] Viral infection and Toll-like receptor agonists induce a differential expression of type,I and , interferons in human plasmacytoid and monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2004Eliana Abstract In humans, the type,I interferon (IFN) family consists of 13 IFN-, subtypes, IFN-, and IFN-o the newly discovered IFN-like family consists of IFN-,1, -,2 and -,3. We have investigated the expression of type,I and , IFN genes following virus infections or Toll-like receptor (TLR) triggering in monocyte-derived DC (MDDC) and plasmacytoid DC (pDC). We found thatall IFN-,, -,, -o and -, subtypes are expressed in influenza-virus-infected MDDC or pDC. Conversely, differential type,I IFN gene transcription was induced in MDDC and pDC stimulated by specific TLR agonists. TLR-9 stimulation by CpG DNA induced the expression of all IFN-,, -,, -o and -, subtypes in pDC, whereas TLR-4 stimulation by LPS, or TLR-3 stimulation bypoly I:C, induced only IFN-, and IFN-, gene expression in MDDC. The expression pattern of IFN regulatory factor (IRF)-5 and IRF-7 in MDDC and pDC was also determined. IRF-5 was constitutively expressed in the two DC subsets whereas IRF-7 was constitutive in pDC but its expression was induced along MDDC maturation. Overall, our data indicate that the coordinated expression of IFN-, with IFN-, would be of crucial importance for the maturation of DC. [source] Instructive cytokine signals in dendritic cell lineage commitmentIMMUNOLOGICAL REVIEWS, Issue 1 2010Michael A. Schmid Summary:, Clarifying the signals that lead to dendritic cell (DC) development and identifying cellular intermediates on their way to DC differentiation are essential steps to understand the dynamic regulation of number, localization, and functionality of these cells. In the past decade, much knowledge on cytokines, transcription factors, and successive progenitors involved in steady-state and demand-adapted DC development was gained. From the stage of multipotent progenitors, DCs are generated from Flt3+ intermediates, irrespective of lymphoid or myeloid commitment, making fms-related tyrosine kinase 3 ligand one of the major regulators for DC development. Additional key cytokines involved are granulocyte,macrophage colony-stimulating factor (GM-CSF) and M-CSF, with each being essential for particular DC subsets and leading to specific activation of downstream transcription factors. In this review, we seek to draw an integrative view on how instructive cytokine signals acting on intermediate progenitors might lead to the generation of specific DC subsets in steady-state and during inflammation. We hypothesize that the lineage potential of a progenitor might be determined by the set of cytokine receptors expressed that make it responsive to further receive lineage instructive signals. Commitment to a certain lineage might consequently occur when lineage-relevant cytokine receptors are further upregulated and others for alternative lineages are lost. Along this line, we emphasize the role that diverse microenvironments have in influencing the generation of DC subsets with specific functions throughout the body. [source] Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigensIMMUNOLOGICAL REVIEWS, Issue 1 2004William R. Heath Summary:, Cross-presentation involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway. This process is primarily performed by dendritic cells (DCs), which are not a single cell type but may be divided into several distinct subsets. Those expressing CD8, together with CD205, found primarily in the T-cell areas of the spleen and lymph nodes, are the major subset responsible for cross-presenting cellular antigens. This ability is likely to be important for the generation of cytotoxic T-cell immunity to a variety of antigens, particularly those associated with viral infection, tumorigenesis, and DNA vaccination. At present, it is unclear whether the CD8,-expressing DC subset captures antigen directly from target cells or obtains it indirectly from intermediary DCs that traffic from peripheral sites. In this review, we examine the molecular basis for cross-presentation, discuss the role of DC subsets, and examine the contribution of this process to immunity, with some emphasis on DNA vaccination. [source] Differential CD4+ T-cell memory responses induced by two subsets of human monocyte-derived dendritic cellsIMMUNOLOGY, Issue 3 2007Sandra Bajaña Summary Dendritic cells (DC) are powerful inducers of primary T-cell responses, but their role in secondary responses has not been extensively analysed. Here, we address the role of two DC subsets derived from human CD16+ (16+ mDC) or CD16, (16, mDC) monocytes on the reactivation of memory responses. CD4+ CD45RA, memory T cells were obtained from adult blood donors, and central (TCM) and effector (TEM) memory T cells were isolated by fluorescence-activated cell sorting with anti-CCR7 antibodies. The 16+ mDC and 16, mDC were cocultured with autologous lymphocytes, either unpulsed or loaded with purified protein derivatives of Mycobacterium tuberculosis (PPD) or tetanus toxoid (TT), and were analysed for up to 8 days. Over a range of doses, 16+ mDC drove stronger T-cell proliferative responses against both antigens. Overall, antigen-specific memory cells tended to acquire a phenotype of TEM at later time-points in the culture, whereas cells that had completed fewer cycles of division were similar to TCM. The 16+ mDC induced higher rates of proliferation on both TCM and TEM lymphocytes than 16, mDC. This phenomenon was not related to the ability of both DC to induce CD25 expression on T cells, to lower secretion of interleukin-2, or to raise production of interleukin-10 during T-cell/16, mDC cocultures. The induction of TCM effector capacity in terms of interferon-, production was faster and more pronounced with 16+ mDC, whereas both DC had similar abilities with TEM. In conclusion, these data might reveal new potentials in vaccination protocols with 16+ mDC aimed at inducing strong responses on central memory T cells. [source] Prostaglandin E2 is a negative regulator on human plasmacytoid dendritic cellsIMMUNOLOGY, Issue 1 2006Yonsu Son Summary 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-, production by PDCs in response to virus or cytosine,phosphate,guanosine, it inhibited interelukin-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-,-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. [source] Review article: Kidney dendritic cells: Their role in homeostasis, inflammation and transplantationNEPHROLOGY, Issue 7 2009NATASHA M ROGERS SUMMARY: There is definitive experimental proof that a lattice of dendritic cells (DC) exist within the renal parenchyma. Kidney-resident DC (KDC) are an important constituent of passenger leucocytes that initiate the direct component of allograft rejection in transplantation and form a central element of the innate immune response following injurious stimuli to the kidney. DC are recruited to the kidney in pathophysiological states such as glomerulonephritis and ischaemia,reperfusion injury. However, the exact mechanism for engaging and attracting DC to infectious and transplant antigens, and whether specific DC subsets are involved remains unresolved. In addition, the extent to which resident and infiltrating DC contribute to the propagation of injury or rejection is also unclear. Despite consistently expanding published work regarding DC location, phenotype and function, there are a number of deficiencies in our knowledge base, particularly in relation to KDC. [source] Dendritic Cell Deficiency in the Blood of Kidney Transplant Patients on Long-Term Immunosuppression: Results of a Prospective Matched-Cohort StudyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2005Holger Hackstein Evidence from in vitro studies suggests that immunosuppressive drugs interfere with key functions of dendritic cells (DCs), but the in vivo relevance of these findings is elusive. We prospectively analyzed the major DC precursor subsets in the blood of kidney transplant recipients on long-term immunosuppression (,1 year). A total of 87 patients were compared to 87 age- and sex-matched controls. Total DC numbers and the precursor subsets, myeloid type 1 DCs, myeloid type 2 DCs (mDC1, mDC2) and plasmacytoid DCs (pDCs) were identified by four color flow cytometry. Long-term immunosuppression was associated with significant reduction of all major DC subsets in comparison to healthy controls (mDC1 p < 0.001; mDC2 p < 0.0001; two-tailed Mann-Whitney U -test) with the strongest negative impact on pDCs (p < 0.00001). In contrast, total leukocyte numbers were not significantly affected. Analysis of the relative impact of different agents revealed a significant impact of prednisolone on pDCs (p = 0.009) and mDCs2 (p = 0.006). The functional relevance of pDC deficiency was confirmed independently by Interferon-alpha analysis after Toll-like receptor 7 (p , 0.001) and 9 (p < 0.05) stimulation. These results indicate for the first time a profound negative impact of long-term immunosuppression on major DC subsets in kidney transplant recipients. DC deficiency may have important implications with respect to viral infections and tumor development. [source] Dendritic Cell Subset Ratio in Peripheral Blood Correlates with Successful Withdrawal of Immunosuppression in Liver Transplant PatientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2003George V. Mazariegos Human dendritic cell (DC) subsets appear to play distinct roles in the induction and regulation of immune responses. While monocytoid DC (DC1) induce T-helper (Th) 1-type responses, plasmacytoid DC (DC2) have been reported to selectively induce Th2 responses. In blood, their precursors (p) can be identified as HLA-DR+ lineage, cells that are further characterized as CD11c+ CD123,/lo (IL-3R,,/lo) (pDC1) or as CD11c, CD123hi (pDC2) by rare event, flow cytometric analysis. We compared the incidences of pDC1 and pDC2 in peripheral blood mononuclear cell populations isolated from normal healthy controls and from 3 groups of clinically stable liver transplant patients. Group A had been successfully withdrawn from immunosuppression, whereas group B were undergoing prospective drug weaning and on minimal anti-rejection therapy. In group C, drug withdrawal had either failed or never been attempted and patients were on maintenance immunosuppression. Assessment of DC subsets and the pDC2 : pDC1 ratio showed good intra-and interassay reproducibility. Compared with patients in group C, those in groups A and B demonstrated a significantly higher relative incidence of pDC2 and a lower incidence of pDC1 , similar to those values observed in normal healthy controls. Moreover, the pDC2 : pDC1 ratio was significantly higher in patients undergoing (successful) weaning and in those off immunosuppression compared with patients on maintenance immunosuppression. [source] Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasuresAPMIS, Issue 5-6 2009ALEXANDER RÖLLE Human cytomegalovirus (HCMV) is a ,-herpesvirus that infects the majority of the population during early childhood and thereafter establishes life-long latency. Primary infection as well as spontaneous reactivation usually remains asymptomatic in healthy hosts but can, in the context of systemic immunosuppression, result in substantial morbidity and mortality. HCMV counteracts the host immune response by interfering with the recognition of infected cells. A growing body of literature has also suggested that the virus evades the immune system by paralyzing the initiators of antiviral immune responses , the dendritic cells (DCs). In the current review, we discuss the effects of CMV (HCMV and murine CMV) on various DC subsets and the ensuing innate and adaptive immune responses. The impact of HCMV on DCs has mainly been investigated using monocyte-derived DCs, which are rendered functionally impaired by infection. In mouse models, DCs are targets of viral evasion as well, but the complex cross-talk between DCs and natural killer cells has, however, demonstrated an instrumental role for DCs in the control and clearance of viral infection. Fewer studies address the role of peripheral blood DC subsets, plasmacytoid DCs and CD11c+ myeloid DCs in the response against HCMV. These DCs, rather than being paralyzed by HCMV, are largely resistant to infection, mount a vigorous first-line defense and induce T-cell responses to the virus. This possibly provides a partial explanation for an intriguing conundrum: the highly efficient control of viral infection and reactivation in immunocompetent hosts in spite of multi-layered viral evasion mechanisms. [source] Novel role of plasmacytoid dendritic cells in humans: Induction of interleukin-10,producing treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapyARTHRITIS & RHEUMATISM, Issue 1 2010Melina Kavousanaki Objective Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting. Methods DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25, T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay. Results Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25, T cells into interleukin-10,secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC,primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner. Conclusion These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation. [source] Tissue targeting of anti-RNP autoimmunity: Effects of T cells and myeloid dendritic cells in a murine modelARTHRITIS & RHEUMATISM, Issue 2 2009Eric L. Greidinger Objective To explore the role of immune cells in anti-RNP autoimmunity in a murine model of pneumonitis or glomerulonephritis, using adoptive transfer techniques. Methods Donor mice were immunized with 50 ,g of U1,70-kd small nuclear RNP fusion protein and 50 ,g of U1 RNA adjuvant. Whole splenocytes as well as CD4+ cell and dendritic cell (DC) subsets from the immunized mice were infused into naive syngeneic recipients. Anti-RNP and T cell responses were assessed by immunoblotting, enzyme-linked immunosorbent assay, and flow cytometry. Development of renal or lung disease was assessed by histology and urinalysis. Results Unfractionated splenocytes from donor mice without proteinuria induced predominantly lung disease in recipients (8 [57%] of 14 versus 2 [14%] of 14 developing renal disease; P = 0.046). However, infusion of CD4+ cells from donors without proteinuria induced renal disease more frequently than lung disease (7 [70%] of 10 versus 2 [20%] of 10; P = 0.01); adoptive transfer of RNP+CD4+ T cells from short-term culture yielded similar results (renal disease in 8 [73%] of 11 recipients versus lung disease in 3 [27%] of 11). Cotransfer of splenic myeloid DCs and CD4+ T cells from immunized donors prevented induction of renal disease in all 5 recipients (P = 0.026 versus recipients of fresh CD4+ cells alone), although lung disease was still observed in 1 of 5 mice. Transfer of myeloid DCs alone from immunized donors induced lung disease in 3 (60%) of 5 recipients, without evidence of nephritis. Cotransfer of splenocytes from mice with and those without nephritis led to renal disease in 4 of 5 recipients, without evidence of lung disease. Conclusion These findings indicate that RNP+CD4+ T cells are sufficient to induce anti-RNP autoimmunity, tissue targeting in anti-RNP autoimmunity can be deviated to either a renal or pulmonary phenotype depending on the presence of accessory cells such as myeloid DCs, and DC subsets can play a role in both propagation of autoimmunity and end-organ targeting. [source] Either interleukin-12 or interferon-, can correct the dendritic cell defect induced by transforming growth factor ,1 in patients with myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Ross Brown Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor ,1 (TGF,1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF,1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- , neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123,) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- , to future immunotherapy trials involving these patients should be considered. [source] Dendritic cells in the recognition of intestinal microbiotaCELLULAR MICROBIOLOGY, Issue 4 2006Jan Hendrik Niess Summary Mucosal dendritic cells (DCs) constantly survey the luminal microenvironment which contains commensal microbiota and potentially harmful organisms regulating pathogen recognition and adaptive as well as innate defense activation. Distinct mechanisms are beginning to emerge by which intestinal antigen sampling and handling is achieved ensuring specificity and contributing to redundancy in pathogen detection. Distinct DC subsets are associated with these mechanisms and regulate specific innate or adaptive immune responses to help distinguish between commensal microbiota, pathogens and self antigens. Understanding DC biology in the mucosal immune system may contribute to the unraveling of infection routes of intestinal pathogens and may aid in developing novel vaccines and therapeutic strategies for the treatment of infectious and inflammatory diseases. [source] CD1a expression defines an interleukin-12 producing population of human dendritic cellsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009M. Cernadas Summary Human and murine dendritic cell (DC) subsets are often defined by phenotypic features that predict their functional characteristics. In humans and mice, DC have been shown to have the ability to polarize naive CD4 T cells to a T helper type 1 (Th1) or Th2 phenotype. However, human myeloid DC generated from monocytes (monocyte-derived DC) have often been regarded as a homogeneous population, both phenotypically and functionally. Monocytes give rise to subpopulations of DC in vitro that can be separated on the basis of their expression of CD1a, a well-described DC subset marker. Importantly, we show that the CD1a+ DC subset produces significant quantities of interleukin-12p70 (IL-12p70) upon stimulation and, similar to the murine CD8,+ DC subset, can polarize naive CD4+ T cells to a Th1 phenotype. In contrast, CD1a, DC, similar to murine CD8,, DC, do not produce significant amounts of IL-12p70 upon stimulation or polarize T cells to a Th1 phenotype. Like monocyte-derived DC, CD1a+ and CD1a, DC subsets obtained from CD34+ haematopoietic progenitors under distinct culture conditions were found to have these same features, suggesting that CD1a expression is a marker for myeloid DC that are a major source of IL-12 and Th1 CD4+ T cell polarization in man. [source] | ||||||||||