| Dendritic cell | |
|---|---|
 Dendritic cells in skin | |
 Artistic rendering of the surface of a human dendritic cell illustrating sheet-like processes that fold back onto the membrane surface. | |
| Details | |
| System | Immune system |
| Identifiers | |
| Latin | cellula dendritiformis |
| MeSH | D003713 |
| TH | H1.00.01.0.00038 |
| FMA | 83036 |
| Anatomical terminology | |
Adendritic cell (DC) is anantigen-presenting cell (also known as anaccessory cell) of themammalianimmune system. A dendritic cell's function is to processantigen material andpresent it on the cell surface to theT cells of the immune system. They act as messengers between theinnate andadaptive immune systems.[1]
Dendritic cells are present in tissues that are in contact with the body's external environment, such as theskin, and the inner lining of thenose,lungs,stomach andintestines. They can also be found in an immature and mature state in theblood. Once activated, they migrate to thelymph nodes, where they interact withT cells andB cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, thedendrites, that give the cell its name (δένδρον or déndron being Greek for 'tree'). While similar in appearance to the dendrites ofneurons, these are structures distinct from them. Immature dendritic cells are also calledveiled cells, as they possess large cytoplasmic 'veils' rather than dendrites.[citation needed]
Dendritic cells were first described byPaul Langerhans (henceLangerhans cells) in the late nineteenth century. The termdendritic cells was coined in 1973 byRalph M. Steinman andZanvil A. Cohn.[2] For discovering the central role of dendritic cells in the adaptive immune response,[3] Steinman was awarded theAlbert Lasker Award for Basic Medical Research in 2007[4] and theNobel Prize in Physiology or Medicine in 2011.[5]
Themorphology of dendritic cells results in a very large surface-to-volume ratio. That is, the dendritic cell has a very large surface area compared to the overall cell volume.
The most common division of dendritic cells isconventional dendritic cells (a.k.a.myeloid dendritic cells) vs.plasmacytoid dendritic cell (most likely oflymphoid lineage) as described in the table below:
| Name | Description | Secretion | Toll-like receptors[6] |
|---|---|---|---|
| Conventional dendritic cell (cDC) (previously calledmyeloid dendritic cell (mDC)) | Most similar tomonocytes. mDC are made up of at least two subsets:
| Interleukin 12 (IL-12),Interleukin 6 (IL-6), TNF, chemokines | TLR 2,TLR 4 |
| Plasmacytoid dendritic cell (pDC) | Look likeplasma cells, but have certain characteristics similar to myeloid dendritic cells.[7] | Can produce high amounts ofinterferon-α[8] and were previously calledinterferon-producing cells.[9] | TLR 7,TLR 9 |
The markersBDCA-2,BDCA-3, andBDCA-4 can be used to discriminate among the types.[10]
Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors, respectively, and thus are ofhematopoietic origin. By contrast,follicular dendritic cells (FDC) are probably ofmesenchymal rather thanhematopoietic origin and do not expressMHC class II, but are so named because they are located in lymphoid follicles and have long "dendritic" processes.
The blood DCs are typically identified and enumerated inflow cytometry. Three types of DCs have been defined in human blood: the CD1c+ myeloid DCs, theCD141+ myeloid DCs and theCD303+ plasmacytoid DCs. This represents the nomenclature proposed by the nomenclature committee of theInternational Union of Immunological Societies.[11]Dendritic cells that circulate in blood do not have all the typical features of their counterparts in tissue, i.e. they are less mature and have no dendrites. Still, they can perform complex functions including chemokine-production (in CD1c+ myeloid DCs),cross-presentation (in CD141+ myeloid DCs), and IFNalpha production (in CD303+ plasmacytoid DCs).
In some respects, dendritic cells culturedin vitro do not show the same behaviour or capability as dendritic cells isolatedex vivo. Nonetheless, they are often used for research as they are still much more readily available than genuine DCs.
Dendritic cells are derived fromhematopoietic bone marrow progenitor cells (HSC). These progenitor cells initially transform into immature dendritic cells. These cells are characterized by high endocytic activity and low T-cell activation potential. Immature dendritic cells constantly sample the surrounding environment for pathogens such asviruses andbacteria. This is done throughpattern recognition receptors (PRRs) such as thetoll-like receptors (TLRs). TLRs recognize specific chemical signatures found on subsets of pathogens. Immature dendritic cells may alsophagocytose small quantities of membrane from live own cells, in a process called nibbling. Once they have come into contact with a presentable antigen, they become activated into mature dendritic cells and begin to migrate to alymph node. Immature dendritic cells phagocytose pathogens and degrade theirproteins into small pieces and upon maturation present those fragments at their cell surface usingMHC molecules. Simultaneously, they upregulate cell-surface receptors that act asco-receptors in T-cell activation such asCD80 (B7.1),CD86 (B7.2), andCD40 greatly enhancing their ability to activate T-cells. They also upregulateCCR7, a chemotactic receptor that induces the dendritic cell to travel through theblood stream to thespleen or through thelymphatic system to alymph node. Here they act asantigen-presenting cells: they activatehelper T-cells andkiller T-cells as well asB-cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals. Dendritic cells can also induce T-cell tolerance (unresponsiveness). Certain C-type lectin receptors (CLRs) on the surface of dendritic cells, some functioning as PRRs, help instruct dendritic cells as to when it is appropriate to induce immune tolerance rather than lymphocyte activation.[13]
Every helper T-cell is specific to one particular antigen. Only professionalantigen-presenting cells (APCs: macrophages, B lymphocytes, and dendritic cells) are able to activate a resting helper T-cell when the matching antigen is presented. However, in non-lymphoid organs, macrophages and B cells can only activatememory T cells[citation needed] whereas dendritic cells can activate both memory andnaive T cells, and are the most potent of all the antigen-presenting cells. In the lymph node and secondary lymphoid organs, all three APCs can activate naive T cells. Whereas mature dendritic cells are able to activate antigen-specific naive CD8+ T cells, the formation of CD8+ memory T cells requires the interaction of dendritic cells with CD4+helper T cells.[14] This help from CD4+ T cells additionally activates the matured dendritic cells and licenses (empowers) them to efficiently induce CD8+ memory T cells, which are also able to be expanded a second time.[14][15] For this activation of CD8+, concurrent interaction of all three cell types, namely CD4+ T helper cells, CD8+ T cells and dendritic cells, seems to be required.[15]
As mentioned above, mDC probably arise frommonocytes, white blood cells which circulate in the body and, depending on the right signal, can turn into either dendritic cells ormacrophages. The monocytes in turn are formed from stem cells in thebone marrow.Monocyte-derived dendritic cells can be generated in vitro fromperipheral blood mononuclear cell (PBMCs). Plating of PBMCs in a tissue culture flask permits adherence of monocytes. Treatment of these monocytes with interleukin 4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF) leads to differentiation to immature dendritic cells (iDCs) in about a week. Subsequent treatment with tumor necrosis factor (TNF) further differentiates the iDCs into mature dendritic cells. Monocytes can be induced to differentiate into dendritic cells by a self-peptide Ep1.B derived fromapolipoprotein E.[16] These are primarilytolerogenic plasmacytoid dendritic cells.[17]
In mice, it has been estimated that dendritic cells are replenished from the blood at a rate of 4000 cells per hour, and undergo a limited number of divisions during their residence in the spleen over 10 to 14 days.[18]
The exact genesis and development of the different types and subsets of dendritic cells and their interrelationship is only marginally understood at the moment[when?], 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 2000 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.[citation needed]
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell–cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the membrane proteins of theB7 family of the dendritic cell withCD28 present on thelymphocyte. However, thecell–cell interaction can also take place at a distance viacytokines.[citation needed]
For example, stimulating dendritic cellsin vivo with microbial extracts causes the dendritic cells to rapidly begin producingIL-12.[19] IL-12 is a signal that helps send naiveCD4 T cells towards aTh1 phenotype. 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. The plasmacytoid DC has the ability to produce huge amounts oftype-1 IFNs, which recruit more activated macrophages to allow phagocytosis.[20]
Blastic plasmacytoid dendritic cell neoplasm is a rare type ofmyeloid cancer in which malignant pDCs infiltrate the skin, bone marrow, central nervous system, and other tissues. Typically, the disease presents with skin lesions (e.g. nodules, tumors,papules, bruise-like patches, and/or ulcers) that most often occur on the head, face, and upper torso.[21] This presentation may be accompanied by cPC infiltrations into other tissues to result in swollenlymph nodes, enlarged liver, enlarged spleen, symptoms ofcentral nervous system dysfunction, and similar abnormalities in breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, and/or testes.[22] The disease may also present as a pDCleukemia, i.e. increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) and bone marrow and evidence (i.e.cytopenias) ofbone marrow failure.[22] Blastic plasmacytoid dendritic cell neoplasm has a high rate of recurrence following initial treatments with variouschemotherapy regimens. In consequence, the disease has a poor overall prognosis and newerchemotherapeutic and novelnon-chemotherapeutic drug regimens to improve the situation are under study.[23]
HIV, which causesAIDS, can bind to dendritic cells via various receptors expressed on the cell. The best studied example isDC-SIGN (usually on MDC subset 1, but also on other subsets under certain conditions; since not all dendritic cell subsets express DC-SIGN, its exact role in sexual HIV-1 transmission is not clear)[citation needed]. When the dendritic cell takes up HIV and then travels to the lymph node, the virus can be transferred to helper CD4+ T-cells,[24] contributing to the developing infection. This infection of dendritic cells by HIV explains one mechanism by which the virus could persist after prolongedHAART.[citation needed]
Many other viruses, such as theSARS virus, seem to use DC-SIGN to 'hitchhike' to its target cells.[25] However, most work with virus binding to DC-SIGN expressing cells has been conducted using in vitro derived cells such as moDCs. The physiological role of DC-SIGN in vivo is more difficult to ascertain.
Dendritic cells are usually not abundant at tumor sites, but increased densities of populations of dendritic cells have been associated with better clinical outcome, suggesting that these cells can participate in controlling cancer progression.[26][27] Lung cancers have been found to include four different subsets of dendritic cells: three classical dendritic cell subsets and one plasmacytoid dendritic cell subset.[28] At least some of these dendritic cell subsets can activate CD4+ helper T cells andCD8+ cytotoxic T cells, which are immune cells that can also suppresstumor growth. However, dendritic cell activity is commonly suppressed by regulatory T cells and multiple other factors.[29] Dendritic cell stimulating treatments, such as dendritic cell based vaccinations, have been emerging as a treatment with varying success.[30] In experimental models, dendritic cells have also been shown to contribute to the success of cancer immunotherapies, for example with the immune checkpoint blocker anti-PD-1.[31][32]
Altered function of dendritic cells is also known to play a major or even key role inallergy andautoimmune diseases likelupus erythematosus and inflammatory bowel diseases (Crohn's disease andulcerative colitis).[33][34][35]
The above applies to humans. In other organisms, the function of dendritic cells can differ slightly. However, the principal function of dendritic cells as known to date is always to act as an immune sentinel. They survey the body and collect information relevant to the immune system, they are then able to instruct and direct the adaptive arms to respond to challenges.
In addition, an immediate precursor to myeloid and lymphoid dendritic cells of the spleen has been identified.[36] This precursor, termed pre-DC, lacks MHC class II surface expression, and is distinct from monocytes, which primarily give rise to DCs in non-lymphoid tissues.
Dendritic cells have also been found in turtles.[37]
Dendritic cells have been found in rainbow trout (Oncorhynchus mykiss) and zebrafish (Danio rerio) but their role is still not fully understood[38]
Definitions from Wiktionary
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