Other important cytokine is granulocyte and macrophage colony-stimulating factor Figure 1. It has been observed that it can induce the differentiation of DCs in vitro and in vivo Figure 2 ;however, GM-CSF-deficient mice show normal levels of resident DCs of lymphoid organs, although there were some alterations in the levels of resident mucous or migratory DCs.
In spite of the above, GM-CSF has been widely used in the differentiation of DCs in vitro that are subsequently used for therapeutic purposes [ 11 , 12 ]. Differentiation of DCs from bone marrow precursors.
The figure shows the differentiation of DCs from bone marrow precursor. The presence of poorly adherent cells with a great number of long and thin extensions is observed. F A large number of extensions are observed in a DC stained with toluidine blue. The arrows point to DCs. On the other hand, another cytokine involved in DCs differentiation is macrophage colony-stimulating factor Figure 1.
Nevertheless, knockout mice for M-CSF and its receptor did not show changes in DC levels in lymphoid organs, although there were decreased levels of monocytes and Langerhans cells LCs [ 13 ]. The differentiation of DCs is carried out from various cell progenitor populations located in bone marrow Figure 1.
Multiple experiments have been conducted in order to characterize the different populations that can give rise to DCs, macrophages, or lymphocytes. In vivo assays in irradiated mice showed that the inoculation of MDPs was directly involved in the differentiation of DCs and macrophages especially in lymphoid organs [ 13 , 14 ].
Ly6c is a monocyte marker. On the other hand, the DCs differentiation in human is a little different from its counterpart in mice Figure 1. When these cells initiate the expression of M-CSFR, the phenotype changes and they are called macrophages and DCs progenitor, population with the capacity of differentiation to macrophages and DCs. There is a great variety of DCs with different phenotypes and location. In general, DCs have been divided into conventional, plasmacytoid, and monocyte-derived [ 1 ].
Another group of DCs derived from monocytes mDCs appears only when there is an inflammation. Langerhans cells, normal residents of the epidermis and epithelia, are not considered on the same lineage of the DCs mentioned above, since they originate from precursor cells that migrated to the skin before birth and differentiated into LCs during the first week of life [ 18 ].
In relation to the origin of the DCs, they all differ from bone marrow progenitor cells that have, as their common denominator, the expression of Flt3 and sometimes M-CSFR [ 19 ]. DCs are more numerous in lymphoid organs and epithelia. In addition, DCs can express various molecular markers depending on their location.
Figure 3 shows to which cluster of cDCs each cell belongs. It is necessary to consider the phenotype and particular location of DCs in relation to their function on that tissue.
For example, the degree of maturation of DCs in lymphoid organs is different from that of DCs in other tissues, since DCs are sentinel cells responsible for the recognition of pathogens and signals of tissue damage, which induces their migration to lymphoid organs to carry out the activation of different subsets of T, natural killer NK , NKT, and B lymphocytes.
It has also been studied and analyzed for a long time that the inflammatory or tolerogenic microenvironment induced by the cytokines present in tissues is essential in the determination of the functions that DCs can have [ 17 ]. Dendritic cells location and phenotype. It is important to know the types of DCs located in the organism, as well as the cytokines involved in its activation, so the following explains the different types of DCs located in lymphoid organs, skin, gut, and blood Figure 4.
DCs at different locations. Arrows in B point to basal DCs. In A , a few Langerin-positive cells asterisks are observed in the dermis. In E , a histological section of spleen showing Fascin-positive DCs is depicted. DCs are located in the T-dependent zone of the white pulp. DCs are classified into subsets according to CD11b marker expression. Using a new strategy named retroviral barcoding, it was determined that cDCs have a great similarity to spleen DCs and progenitors of bone marrow DCs [ 1 ].
Both DC subsets are home to the thymus through blood vessels, but the specific tissues that originated from have not been comprehensively determined. Multiple cell lines can be localized in the blood, such as granulocytes, monocytes, and lymphocytes, and to study blood DCs, several lineage markers Lin , such as CD3, CD19, CD14, CD20, and CD56, are used to separate populations of DCs by means of flow cytometry assays [ 24 ].
Both types of DCs are negative for Lin markers. In epidermis and dermis, different types of DCs can be found. In humans, the expression of CD1a has also been observed, but not in mice. Langerhans cells were considered to be bone marrow dependent; however, it has been observed that LCs may have two distinct embryonic origins: the fetal liver and the yolk sac. In humans, LCs have a phenotype very similar to that of mice, and they may respond to IL The population of pDCs located in the dermis is very low; however, in inflammatory skin diseases such as psoriasis or lupus erythematosus, an increase of this type of skin cells has been observed [ 29 ].
There is a second type of DCs that are also located in the lamina propria, but which express the markers CD and CD11b, although CD is expressed in low levels. As previously mentioned, the DC differentiation is a process occurring in bone marrow.
As a result of this process, different DC populations not only acquire different phenotypes but also colonize different tissues and perform different functions [ 31 ]. Mature CDs produce differentially cytokines related to promote the different immune responses Th1, Th2, Th17, and Treg. In this section, we describe the patterns of cytokine production, produced by the different subsets of DCs. Human cDCs differentiated from bone marrow precursors in the presence of GM-CSF and IL-4 differentially show not only the expression of mRNA but also the production and release of different cytokines depending on their maturation stage.
Both immature and mature DCs have different cytokine pattern secretion Table 1 [ 17 , 32 ]. It has been observed that the differential expression of cytokines is regulated not only according to the type of DCs but also by the activation pathway. This fact is due to a differential signal on the production of IL which strongly interacts with IL [ 24 , 40 ].
This differential production of cytokines appears to be due to the involvement of IL that acts similarly to IL-4, thus promoting this response Th2 [ 41 , 42 ] Table 1. These cells acquire a tolerogenic activity characterized by an immature phenotype with weak expression of co-stimulatory molecules, but with a differential production of anti- and proinflammatory cytokines.
This production of cytokines by tolerogenic DCs is dependent on the microenvironment in which they are found. Tolerogenic DCs activation pathways with their cytokine secretion profile and phenotype. Since their description, pDCs have produced a great controversy about their origin and function.
Unlike other DCs, pDCs generation is controlled by the expression of the transcription factor E [ 54 ]. In their immature or inactive state, they have a similar appearance to plasmatic cells, lacking dendritic cytoplasmic projections, do not show an ability for uptake and present antigens and produce large amounts of IFN types I and III.
However, when these cells are activated, they rapidly undergo a morphological and functional conversion similar to that of cDCs with a capacity to stimulate T cells [ 2 ]. They are known to share with cDCs not only the same progenitor but also the dependence of some factors for their differentiation as the cytokine FMS-related tyrosine kinase 3 ligand Flt3L and interferon-regulating factor 8 IRF8 [ 56 ].
Like other DCs, pDCs are deficient of lymphocytic lineage markers. The regulatory capacity of pDCs involves the expression of the indoleamine 2,3-dioxygenase IDO enzyme [ 52 ], a suboptimal presentation of antigens, and the induction of Treg cells [ 57 , 58 ]. DCs are capable of capturing and processing antigens very efficiently and for this they possess several molecules that have been identified and are discussed below. In general, two antigen-processing pathways have been defined, the endocytic pathway and the cytosolic pathway, through which exogenous and endogenous antigens are presented, respectively [ 59 ].
Exogenous antigens, such as those derived from bacteria, are captured by immature DCs by means of endocytosis, phagocytosis, or both, through different molecules such as Fc receptors of IgG or lectins such as CD, which guides their internalization into endocytic compartments with increasing acidity: slightly acidic early endosomes, moderately acidic endolysosomes, and very acidic late endolysosomes [ 60 ].
The late endolysosomes are very rich in MHCII and it is in these compartments where the antigens are degraded in polypeptides of 13—18 residues by some acidic proteases such as thiol and aspartyl cathepsins specific for the substrate [ 61 , 62 ]. This degradation is regulated by the concentrations of cathepsin S and its inhibitor endogenous cystatin C. Figure 1. Exploiting the immune-regulatory capacities of DCs holds great promise for the treatment of cancer , autoimmune diseases and the prevention of transplant rejection.
In the case of cancer, tumours have been shown to suppress DCs by secreting anti-inflammatory cytokines such as IL , and therefore conditioning the local DCs to form suppressive T cells. DC vaccines generated in this way are generally safe with minimal side effects, and have proven to be feasible, and effective in some patients.
Other strategies exploiting DCs in various disorders have also been described and are being investigated in clinical trials. Register Log in. Dendritic Cells Download Dendritic Cells. DCs linking innate and adaptive immunity Since DCs have numerous cytoplasmic processes, they have a high surface area permitting intimate contact with a large number of surrounding cells, e.
Related Articles B Cells. Dendritic Cells. The exact genesis and development of the different types and subsets of dendritic cells and their interrelationship is only marginally understood at the moment, as dendritic cells are so rare and difficult to isolate that only in recent years they have become subject of focused research. Distinct surface antigens that characterize dendritic cells have only become known from on; before that, researchers had to work with a 'cocktail' of several antigens which, used in combination, result in isolation of cells with characteristics unique to DCs.
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the receptor CD40 of the dendritic cell with CD40L present on the lymphocyte. However, the cell-cell interaction can also take place at a distance via cytokines.
For example, stimulating dendritic cells in vivo with microbial extracts causes the dendritic cells to rapidly begin producing IL The ultimate consequence is priming and activation of the immune system for attack against the antigens which the dendritic cell presents on its surface. However, there are differences in the cytokines produced depending on the type of dendritic cell. When the dendritic cell takes up HIV and then travels to the lymph node, the virus is able to move to helper T-cells, and this infection of helper T-cells is the major cause of disease.
This knowledge has vastly altered our understanding of the infectious cycle of HIV since the mids, since in the infected dendritic cells, the virus possesses a reservoir which also would have to be targeted by a therapy.
Altered function of dendritic cells is also known to play a major or even key role in allergy and autoimmune diseases like lupus erythematosus.
The above applies to humans. In other organisms, the function of dendritic cells can differ slightly. For example, in brown rats but not mice , a subset of dendritic cells exists that displays pronounced killer cell-like activity, apparently through its entire lifespan. However, the principal function of dendritic cells as known to date is always to act as the central command and central encyclopedia of the immune response, or similar to servers in a computer network. They collect and store the immune system's "knowledge", enabling them to instruct and direct the adaptive arms in response to challenges.
Morphology, quantitation, tissue distribution". PMID Arthritis Res. J Immunol. Virus Res. CS1 maint: Explicit use of et al. Nature Immunolgy.
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