Dendritic Cell System Research Articles

Myeloid Dendritic Cells Were Expanded and Functionally Stronger in Aplastic Anemia

At present, the activated T cell-mediated destruction of hematopoietic stem/progenitor cells is the widely-recognized pathogenesis of aplastic anemia (AA). As the most important antigen-presenting cells in humans, dendritic cells (DCs) play an important role in the upstream link of immune pathogenesis in AA patients, so it may be the reason for the breakdown of immune tolerance in AA patients. In addition, abatacept, a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) fusion protein, can block T cell activation and function by binding CD80 and CD86 and blocking their interaction with CD28. Thus may be a potential direction for targeting DCs to treat AA. However, relevant reports have not been seen so far. To investigate the potential role of DCs in the pathogenesis of AA, we collected peripheral blood (PB) and bone marrow (BM) and measured the proportion of DCs. Results revealed that compared with healthy donors (HD), the proportion of myeloid DC in PB and BM in AA patients was significantly higher. In contrast, the proportion of plasmacytoid DC decreased significantly. Besides, the expression of CD80 and CD86 on PB DC surface of AA patients was higher than that of HD patients. Next, we cultured monocyte-derived DC in vitro and detected its phenotype and function. We confirmed that compared with HD, the expression rates of the co-stimulatory molecule CD80 and mature molecule CD83 of DC in AA patients were significantly increased, the apoptosis level was significantly decreased, and the ability to promote proliferation of CD3 +, CD4 + and CD8 + T lymphocytes was enhanced. At the same time, AA-DC significantly enhanced the ability of CD4 + T and CD8 + T cells to express CD25 and CD69. In addition, the ability of AA-DC to promote the differentiation of Th0 cells to Th1 and Th17 cells was stronger than HD. The ability to promote the differentiation of Th0 to Treg cells was weaker than HD. To investigate the feasibility of abatacept targeting DC in the treatment of AA, we compared the proportions of CTLA-4 and found the expression of CTLA-4 on CD4 + T cells and Treg cells in PB of AA patients was significantly decreased. Then, our in vitro tests confirmed that abatacept can bind to CD80 on the surface of DC and significantly down-regulate the expression of CD80. Adding abatacept into the co-culture system of DC and CD3 + T lymphocytes significantly inhibited the proliferation of CD3 +, CD4 + and CD8 + T lymphocytes, and significantly inhibited the expression of CD25 and CD69 in CD4 + T and CD8 + T cells. In addition, the ability of DC to promote the secretion of interferon-γ by CD4 + and CD8 + T cells in AA patients was significantly weakened after the addition of abatacept, while the ability to promote the secretion of interleukin-4 by CD4 + and CD8 + T cells was significantly enhanced. Finally, we performed RNA-Seq analysis using DCs cultured in vitro from HD and AA patients and using DC from AA patients added with abatacept to uncover the possible molecular mechanism. Result showed that compared with HD, there were significant differences in the expression levels of 58 genes of DC in patients with AA, including 22 up-regulated genes and 36 down-regulated genes. Go analysis inferred that the differentially expressed genes were mainly concentrated in cell migration, cell chemotaxis, regulation of cytokine production, and immune response. Besides, KEGG pathway analysis implied that the signaling pathway of significant enrichment of differentially expressed genes was cytokine-cytokine receptor interaction, NF-κB signaling pathway, chemokine signaling pathway and IL-17 signaling pathway. Meanwhile, compared with AA patients, after adding abatacept, 1058 genes showed significant differences in expression levels. Go analysis inferred that the differentially expressed genes were mainly concentrated in immune response, cytokine secretion, regulation of hemopoiesis, cell activation, differentiation, proliferation, and adhesion. Moreover, KEGG pathway analysis implied that the signaling pathway enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, NF-κB signaling pathway and Th1, Th2 and Th17 cell differentiation. Our finding revealed the increased number and hyperfunction of DC in AA patients may be involved in the immune pathogenesis of AA. Abatacept can block T cell activation by blocking the DC surface co-stimulatory molecule CD80 and is a promising strategy for AA treatment.

Long Non Coding RNA FOXD3‑AS1 Alleviates Allergic Rhinitis by Elevating the Th1/Th2 Ratio via the Regulation of Dendritic Cells

ABSTRACT This article aimed to explore whether the regulation of Th1/Th2 immune responses by FOXD3-AS1 is associated with dendritic cells (DCs) in allergic rhinitis (AR). HE staining was performed to assess the pathological changes in the nasal mucosa; ELISA was performed to measure the levels of Th1/Th2-related cytokines; flow cytometry was performed to analyze Th1/Th2 cells and MHC-II-, CD80-, and CD86-positive DCs; and qRT‒PCR and western blotting were performed to measure mRNA and protein expression levels, respectively. Our data revealed that LV-FOXD3-AS1 improved AR and increased the Th1/Th2 cell ratio in AR model mice. LV-FOXD3-AS1 further inhibited DC maturation both in vivo and in vitro. Moreover, the coculture system of DCs and CD4+ T cells demonstrated that LV-FOXD3-AS1 increased the Th1/Th2 cell ratio by inhibiting the maturation of DCs. In addition, LV-FOXD3-AS1 reduced the level of phosphorylated STAT6 in DCs derived from healthy mice, and STAT6 overexpression eliminated the inhibitory effect of LV-FOXD3-AS1 on the maturation of DCs. In summary, LV-FOXD3-AS1 ameliorated AR by increasing the Th1/Th2 cell ratio by inhibiting DC maturation via the inhibition of STAT6 phosphorylation. Our data confirmed the protective effect of FOXD3-AS1 in AR and provided a novel idea for the treatment of this disease.

Recombinant human IL-37 inhibited endometriosis development in a mouse model through increasing Th1/Th2 ratio by inducing the maturation of dendritic cells

BackgroundEndometriosis is a serious reproductive and general health consequences. Recombinant human IL-37 (rhIL-37) is an inhibitor of inflammation.MethodsELISA assay was performed to detect the concentration of cytokines. Flow cytometry was used to analyze cell proportion. Besides, qRT-PCR and western blotting assay were used to detect the level of gene and protein, respectively. Transwell co-culture system was used for the co-culture of dendritic cells (DCs) and CD4+T cells.ResultsOur data showed that rhIL-37 inhibited the development of ectopic lesions in the mice with endometriosis, increased Th1/Th2 ratio and induced DCs maturation. The co-culture system of DCs and CD4+T cells demonstrated that rhIL-37 increased Th1/Th2 cell ratio through promoting DCs maturation. Moreover, the expression of IL-4 in the DCs derived from healthy mice was inhibited by rhIL-37 treatment. rhIL-37 increased Th1/Th2 cell ratio through inhibiting IL-4 in DCs. Subsequently, our results proved that rhIL-37 promoted the maturation of DCs via inhibiting phosphorylation of STAT3. Activation of STAT3 could reverse rhIL-37-induced maturation of DCs.ConclusionOverall, rhIL-37 could protect against endometriosis through increasing the ratio of Th1/Th2 cells via inducing DCs maturation and inhibiting IL-4 expression in the DCs. Furthermore, rhIL-37 induced DCs maturation by inhibiting STAT3 phosphorylation. Our data confirmed the protective effect of rhIL-37 in endometriosis. These data may provide a novel idea for the treatment of the disease.Graphical abstract

Staphylococcus succinus 14BME20 Prevents Allergic Airway Inflammation by Induction of Regulatory T Cells via Interleukin-10.

Asthma is a common chronic inflammatory disease, which is characterized by airway hyperresponsiveness (AHR), high serum levels of immunoglobulin (Ig)E, and recruitment of various inflammatory cells such as eosinophils and lymphocytes. Korean traditional fermented foods have been reported to exert beneficial effects against allergic diseases such as asthma and atopic dermatitis. In this study, we investigated whether Staphylococcus succinus strain 14BME20 (14BME20) isolated from doenjang, a traditional high-salt-fermented soybean food of Korea, exerts suppressive effects on allergic airway inflammation in a murine model. Mice were orally administered with 14BME20, then sensitized and challenged with ovalbumin as an allergen. Administration of the 14BME20 significantly suppressed AHR and influx of inflammatory cells into the lungs and reduced serum IgE levels. Moreover, the proportion of T helper type 2 (Th2) cells and the production of Th2 cytokines were decreased in 14BME20-treated mice, whereas dendritic cells (DCs) with tolerogenic characteristics were increased. In contrast, oral administration of 14BME20 increased the proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells and the level of interleukin (IL)-10 in 14BME20-treated mice. Furthermore, 14BME20 induced maturation of tolerogenic DCs, and 14BME20-treated DCs increased Treg cell population in a co-culture system of DCs and CD4+ T cells. The addition of a neutralizing anti-IL-10 mAb to the culture of cells that had been treated with 14BME20 decreased the enhanced Treg cell population, thereby indicating that 14BME20-treated DCs increase Treg cell population via DC-derived IL-10. These results demonstrate that oral administration of 14BME20 suppresses airway inflammation by enhancing Treg responses and suggest that the 14BME20 isolated from doenjang may be a therapeutic agent for allergic asthma.

Bone marrow mesenchymal stem cells inhibit dendritic cells differentiation and maturation by microRNA-23b.

Research on regulation and its mechanism of bone marrow mesenchymal stem cells (BMSCs) on dendritic cells (DCs), which is the initiating factor in immune response has applicable clinical value. Although BMSCs have a significant regulatory effect on the maturation of DCs, its molecular mechanism is still unclear. BMSCs and DCs, were co-cultured by different concentration ratios. Flow cytometry was used to detect the expression of DC markers (CD83, CD11c). Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of related genes in RNA level. Expression of the target proteins was detected with using Western blot assay. miRNA inhibitor and miRNA mimic were used to suppress and up-regulate the expression of the target gene. In this research, our results demonstrated that BMSCs notably inhibited maturation of DCs in the co-culture system of BMSCs and DCs and confirmed that this inhibition is due to overexpression of miR-23b. Furthermore, this research found that miR-23b overexpression inhibited the expression of p50/p65, thus blocked the activation of the NF-κB pathway. In conclusion, BMSCs affected the activation of NF-κB pathway through miR-23b overexpression resulting in inhibition of the maturation and differentiation of DCs.

The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

ABSTRACTTargeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment.Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer.In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information.Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b+ DCs. Conditioned medium of miR-31 overexpressing CD11b+ DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer.Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression.

Altered dendritic cell functions in autoimmune diseases: distinct and overlapping profiles.

Dendritic cells (DCs) are central regulators of the balance between immunity and tolerance, and alteration of the specialized DC system is a common feature of both systemic and tissue-specific autoimmune diseases. Increasing evidence indicates that the heterogeneity and the remarkable functional diversity of DC subsets might be differentially affected in autoimmune disorders, which accounts for different pathologies. This Review discusses recent findings that support this concept and provides a new conceptual overview of the altered function and distribution of DCs in autoimmune disorders. The discussion will focus on systemic lupus erythematosus - a prototype of a multi-organ disease - as well as rheumatoid arthritis and idiopathic inflammatory myopathies, pathologies characterized by tissue-specific lesions. Studies on these diseases have revealed common and disease-specific changes in DC distribution and in critical DC functions, such as phagocytosis, cytokine secretion and migration. An improved understanding of the roles of altered DC distribution and/or disturbed key functions in these autoimmune diseases will pave the way for the development of new therapies aiming at reducing immunogenicity and at enhancing the tolerogenic capacity of DCs. Although some tolerogenic DCs have already been introduced in the clinic, the successful translation of other DC-based therapies will require considerable research efforts.

Functional Specialization of Skin Dendritic Cell Subsets in Regulating T Cell Responses.

Dendritic cells (DC) are a heterogeneous family of professional antigen-presenting cells classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin+ and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance toward harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions toward contact sensitizers, cutaneous pathogens, and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease.

The emerging role of dendritic cells in the host immune response against Helicobacter pylori.

The emerging role of dendritic cells in the host immune response against Helicobacter pylori.

A power surge for cancer immunotherapy

A power surge for cancer immunotherapy

The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting

Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.

Dendritic cells and the malaria pre-erythrocytic stage

Malaria remains one of the main infectious diseases in intertropical regions. The malaria parasite has a complex life cycle in its mammalian host, switching between variable forms as it traverses through different tissues and anatomic locations, either intra- or intercellularly. During its journey, the parasite encounters and interacts with the host immune system, which functions to prevent infections and limit ensuing pathologies. One important component of the host immune system is the dendritic cells (DC) network. DC form a heterogeneous group of pathogen-sensing and antigen-presenting cells that play a crucial role in the initiation of adaptive immunity. Here, we review the known and unknown interactions between the malaria parasites and the DC system, starting from the inoculation of the parasite in the skin up to its exit from the liver, also known as the pre-erythrocytic stage of the infection, and discuss how deciphering these interactions may contribute to our understanding of the Plasmodium parasite biology as well as to the induction of immune protection via vaccination.

Exposure to Nicotine Adversely Affects the Dendritic Cell System and Compromises Host Response to Vaccination

The magnitude of Th1 cells response to vaccination is a critical factor in determining protection from clinical disease. Our previous in vitro studies suggested that exposure to the nicotine component of cigarette smoke skews the differentiation of both human and mouse dendritic cell (DC) precursors into atypical DCs (DCs differentiated ex vivo in the presence of nicotine) lacking parameters essential for the development of Th1-mediated immunity. In this study, we determined the causal relationship between nicotine-induced DC alterations and host response to vaccines. We show that animals exposed to nicotine failed to develop and maintain Ag-specific effector memory Th1 cells and Ab production to protein-based vaccine formulated with Th1 adjuvants. Accordingly, both prophylactic and therapeutic vaccines failed to protect and cure the nicotine-exposed mice from disease. More importantly, we demonstrate the nicotine-induced defects in the biological activities of in vivo DCs as an underlying mechanism. Indeed, i.v. administration of DCs differentiated in the presence of nicotine preferentially promoted the development of Ag-specific IL-4-producing effector cells in the challenged mice. In addition, DC subsets isolated from mice exposed to nicotine produced significantly less cytokines in response to Th1 adjuvants and inadequately supported the development of Ag-specific Th1 cells. Collectively, our studies suggest that nicotine-induced defects in the DC system compromises vaccine efficacy in smokers.

Human 6-sulfo LacNAc (slan) dendritic cells are a major population of dermal dendritic cells in steady state and inflammation

The immune system of the skin has a network of resident dendritic cells (DCs) consisting of epidermal Langerhans cells and various subsets of dermal DCs. We recently reported on a new population of dermal DCs, called slan (6-sulfoLacNAc+) DCs, which have a potent capacity to stimulate Th17/Th1 T-cell responses. To understand the characteristics of slanDCs as a new population of dermal DCs in the context of other DC populations in healthy and psoriatic skin. We immunofluorescently stained skin samples from healthy controls and from patients with psoriasis. Staining healthy skin for DCs showed that slanDCs (CD1a- CD1c- CD11c- CD14- CD163-) were present at a similar frequency to that of CD1c+ CD11c+ CD1a+ CD14- CD163- dermal DCs, which have previously been regarded as the major population of resident DCs. In psoriatic skin, the frequency of slanDCs and CD1c+ DCs was doubled, and the slanDCs expressed CD11c. In-depth analysis of DCs in psoriatic skin by four-colour immunofluorescence analysis showed that the pool of CD11c+ cells could be further subdivided into CD11c+ CD14+ CD163- DCs and CD11c+ CD163+ CD14+ macrophages. SlanDCs, initially described as large population of proinflammatory DCs in blood, are a novel and major part of the resident dermal myeloid DC system in both healthy and inflamed skin.

Cholinergic modulation of dendritic cell function

Dendritic cells (DCs) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes. Acetylcholine (ACh) is the primary parasympathetic neurotransmitter and also a non-neural paracrine factor produced by different cells. Here, we analyzed the expression of the cholinergic system in DCs. We found that DCs express the muscarinic receptors M 3, M 4 and M 5, as well as the enzymes responsible for the synthesis and degradation of ACh, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively. Differentiation of DCs in the presence of the cholinergic agonist carbachol, the synthetic analog of ACh, resulted in an increased expression of HLA-DR and CD86 and the stimulation of TNF-α and IL-8 production. All these effects were prevented by atropine, a muscarinic ACh receptor (mAChR) antagonist. Carbachol, was also able to modulate the function of DCs when added after the differentiation is accomplished; it increased the expression of HLA-DR, improved the T cell priming ability of DCs, and stimulated the production of TNF-α but not IL-12 or IL-10. By contrast, carbachol significantly inhibited the stimulation of HLA-DR expression and the enhancement in the T cell priming ability of DCs triggered by LPS. Interestingly, the TNF-α antagonist etanercept completely prevented the increased expression of HLA-DR induced by carbachol, suggesting that it promotes the phenotypic maturation of DCs by stimulating the production of TNF-α. ACh induced similar effects than carbachol; it stimulated the expression of HLA-DR and the production of TNF-α, while inhibiting the stimulation of HLA-DR expression and IL-12 production triggered by LPS. Similarly, neostigmine, an inhibitor of AChE, also stimulated the expression of HLA-DR and the production of TNF-α by DCs while inhibiting the production of TNF-α and IL-12 triggered by LPS. These results support the existence of an autocrine/paracrine loop through which ACh modulates the function of DCs.

Dendritic Cells

Cancer vaccines have undergone a renaissance because of recent clinical trials showing promising immunologic data and some clinical benefit to patients. Current trials exploiting dendritic cells (DCs) as vaccines have shown durable tumor regressions in a fraction of patients. Clinical efficacy of current vaccines is hampered by myeloid-derived suppressor cells, inflammatory type 2 T cells, and regulatory T cells, all of which prevent the generation of effector cells. To improve the clinical efficacy of DC vaccines, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome regulatory T cells and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the DC system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease.

Harnessing human dendritic cell subsets for medicine

Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.

Harnessing Dendritic Cells to Generate Cancer Vaccines

Passive immunotherapy of cancer (i.e., transfer of T cells or antibodies) can lead to some objective clinical responses, thus demonstrating that the immune system can reject tumors. However, passive immunotherapy is not expected to yield memory T cells that might control tumor outgrowth. Active immunotherapy with dendritic cell (DC) vaccines has the potential to induce tumor-specific effector and memory T cells. Clinical trials testing first-generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. Newer generation DC vaccines are built on the increased knowledge of the DC system, including the existence of distinct DC subsets and their plasticity all leading to the generation of distinct types of immunity. Rather than the quantity of IFN-gamma-secreting CD8(+) T cells, we should aim at generating high-quality, high-avidity, polyfunctional effector CD8(+) T cells able to reject tumors and long-lived memory CD8(+) T cells able to prevent relapse.

How Location Governs Toll‐Like Receptor Signaling

Toll-like receptors (TLRs) are a family of innate immune system receptors responsible for recognizing conserved pathogen-associated molecular patterns (PAMPs). PAMP binding to TLRs initiates intracellular signaling pathways that lead to the upregulation of a variety of costimulatory molecules and the synthesis and secretion of various cytokines and interferons by cells of the innate immune system. TLR-induced innate immune responses are a prerequisite for the generation of most adaptive immune responses, and in the case of B cells, TLRs directly regulate signaling from the antigen-specific B-cell receptor. The outcome of TLR signaling is determined, in part, by the cells in which they are expressed and by the selective use of signaling adaptors. Recent studies suggest that, in addition, both the ligand recognition by TLRs and the functional outcome of ligand binding are governed by the subcellular location of the TLRs and their signaling adaptors. In this review we describe what is known about the intracellular trafficking and compartmentalization of TLRs in innate system's dendritic cells and macrophages and in adaptive system's B cells, highlighting how location regulates TLR function.

Understanding human myeloid dendritic cell subsets for the rational design of novel vaccines

Dendritic cells (DCs) orchestrate a repertoire of immune responses that endows resistance to infection and tolerance to self. Understanding the principles by which DCs control immunity and tolerance has provided a rich basis for studying and improving clinical outcome of human disease treatment. Several features contribute to the complexity of the DC system. Among these, plasticity and existence of subsets are prominent determinants to the quality of the elicited immune responses. Indeed, different DC subsets are distributed in peripheral tissues and the blood and display different microbial receptors, surface molecules and cytokine expression, all of which influence the immunologic outcome. The biologic raison d'être for separate DC subsets has been the focus of many studies including our own and is being reviewed with an emphasis on human skin DCs.