Dendritic cells

Steinman Ralph M., 1973; Langerhans Paul, 1868

Dendritic cells (from Latin dendriticus = "branched") are highly specialized cells of the immune system that develop from common CD34-positive bone marrow progenitor cells and are characterized by a common morphology (star-shaped structure with branched cell extensions) and a common functionality (antigen recognition and antigen presentation). From the bone marrow, their progenitor cells (monocytes) migrate via the bloodstream to peripheral tissues where they undergo differentiation into the final dendritic cell.

Together with monocytes, macrophages and B-lymphocytes, dendritic cells belong to the so-called "professional" antigen-presenting cells (APC) of the immune system and are characterized by the presence of MHC (major histocompatibility complex) class I and II molecules on their surface.

Dendritic cells are the only cells capable of inducing a primary immune response. They are detected in the epidermis(Langerhans cell), but also in lymphoid and other non-lymphoid tissues, such as the pharynx, the upper part of the esophagus, the vagina, the external cervix uteri and the anus. Furthermore, they are very abundant in the mucous membranes of the respiratory and gastrointestinal systems.

Langerhans cells are the dendritic cells of the multilayered squamous epithelia. They were first described in the epidermis by the pathologist Paul Wilhelm Heinrichl Langerhans . Langerhans cells express CD1a, CD207 (Langerin) and electron micr0copically exhibit Birbeck granules.

In humans, the following subpopulations of dendritic cells (DCs) have been described:

• Plasma cytoid dendritic DCs (PDC: CD1a-/CD4+/CD11c-/CD123++), which are derived from lymphoid precursor cells.
• Myeloid dendritic DCs (MDCs) derived from myeloid progenitor cells The MDCs can be divided into:
  • MDC1 (CD1a+/CD4+/CD11c++/CD123+DCs
  • MDC2 (CD1a-/CD4+/CD11c+/CD123-DCs

Further specifications for dendritic cells:

• Plasmacytoid dendritic cells (pDC) are a relatively rare type of dendritic cells in the blood and peripheral lymphatic organs. They express the surface markersCD4+/CD123++, but neither CD11c nor CD14. As part of the innate immune system they express the Toll-like receptors TLR-7 and TLR-9. pDCs release large amounts of TypI interferons (IFN-α and IFN-β) after activation. During HIV or HCV infection, the number of circulating pDCs decreases.
• Dermal (myeloid) dendritic cells, in contrast to plasmacytoid dendritic cells, express CD11c and CD33 and larger amounts of MHC II, but not CD123. The most characteristic marker for DDCs is the marker CD1c (BDCA1). In contrast, CD1a, which is strongly expressed on Langerhans cells, is only weakly represented. Dermal (myeloid) dendritic cells are potent producers of TNF-alpha and interleukin-12 or interleukin-23, depending on the type of antigenic stimulation.
• Inflammatory dendritic cells are derived from CD14+ monocytes and partly from the dendric cells of the peripheral blood. Inflammatory dendritic cells develop reactively in the event of acute or chronic tissue inflammation. They first migrate from the blood into the lesional tissue. There they take on the characteristics of dendritic cells. In healthy, non-inflamed tissue IDCs are completely absent. IDCs later migrate from the inflamed tissue into the draining lymphatic organs, where they present antigens of naive T cells.
• CD141 positive dendritic cells: The CD141+ dendritic cell, also called CD14+DC, is found in the circulating peripheral blood. They react with the antibody BDCA-3, which is directed against the CD141 antigen (= thrombomodulin). Thrombomodulin is a protein that acts as a transmembrane receptor for thrombin in the endothelial cell. Thrombomodulin regulates (prevents) coagulation within an uninjured (physiological) vessel.
• CD1c positive dendritic cell: The CD1c+ dendritic cell, also called CD1c+DC, is mainly found in the submucosa of the conducting airways from the alveolus to the trachea. CD1c+ dendritic cells can also be found in the lung interstitium and in the broncho-alveolar lavage fluid. The CD1c protein, like the other members of the CD1 family, belongs to the MHC-I-like proteins and also shows structural similarities with this molecule. Form beginningCD1c(+) dendritic cells are immunologically and morphologically similar to Langerhans cells. Like Langerhans cells they express Langerin, EpCAM and E-Cadherin. Birbeck granules are also morphologically detectable (Milne P et al. 2014). They play an essential role in the pathogenesis of COPD and bronchial asthma (Tsoumakidou M et al. 2014).
• CD1a+ dendritic cell: CD1a+ dendritic cells (see below CD1a), also called CD1a+DC, are dendritic cells (DCs) expressing Langerin, which, in addition to CD1a expression, form another specific of the Langerhans cell, Birbeck granules. They are located in the conducting airways, but not in the lung interstitium, but also in lymphatic tissue and in the decidua (among other tissues). Their further topographical distribution as well as their specific functional significance (functional demarcation to the Langerhans cells of the skin) is still largely unknown.

Dendritic cells as mediators of immunity: Dendritic cells can effectively scan large areas of tissue for antigens of various types with the help of their star-shaped branches. As immature DCs they continuously take up antigens from the environment via phagocytosis and pinocytosis (self-antigens and antigens of microorganisms) and process them in lysosomal compartments into small peptide fragments to present them to the immune system on the surface in cooperation with MHC class Iand MHC class II molecules. In the immature, non-activated stage, the dendritic cells express only small amounts of MHC class I / MHC class II and costimulatory molecules. Through contact with certain antigens or inflammatory cytokines and chemokines, dendritic cells are stimulated to mature. During this process the dendritic cells increase the expression rate of MHC and costimulatory molecules (e.g. CD40, CD80, CD86). They also secrete proinflammatory and antiviral cytokines (e.g. IL-12). These cytokines serve to activate naïve T cells. Only a single dendritic cell is required to activate 100 to 3000 antigen-specific T cells. Dendritic cells are thus significantly more efficient than other antigen-presenting cells (e.g. monocytes or B-lymphocytes), which is also due to the fact that they are able to present 10 to 100 times the amount of MHC-peptide complexes on their surface than these cells.

Mediators of tolerance (see below immunotolerance): Which cytokines are ultimately released depends on which pattern recognition receptors of the dendritic cells were activated by the antigen contact. It is of great importance for the functionality of the organism that the immune response induced by the dendritic cells remains regulated (does not get out of control), e.g. that it is not directed against self-epitopes of the organism. These auto-antigens are mainly proteins from the body's own cells, which are driven into apoptosis, for example, in the course of physiological cell remodelling processes. Such apoptotic cells are a steady and "random" resource for self-antigens. They are of eminent importance for the maintenance of "self-tolerance". Dendritic cells, which have taken up such endogenous antigens, also migrate into the secondary lymphatic organs and stimulate T cells there. Depending on the differentiation stage of the dendritic cells, this type of stimulation does not result in an (auto-) immune reaction, but in apoptosis, anergy or in the development of regulatory T cells(Tregs) which do not produce pro- but anti-inflammatory cytokines (e.g. IL-10).

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