Dendritic cell
A dendritic cell is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.
Dendritic cells are present in tissues that are in contact with the body's external environment, such as the skin, and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature and mature state in the blood. Once activated, they migrate to the lymph nodes, where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites, that give the cell its name. While similar in appearance to the dendrites of neurons, these are structures distinct from them. Immature dendritic cells are also called veiled cells, as they possess large cytoplasmic 'veils' rather than dendrites.
History
Dendritic cells were first described by Paul Langerhans in the late nineteenth century. The term dendritic cells was coined in 1973 by Ralph M. Steinman and Zanvil A. Cohn. For discovering the central role of dendritic cells in the adaptive immune response, Steinman was awarded the Albert Lasker Award for Basic Medical Research in 2007 and the Nobel Prize in Physiology or Medicine in 2011.Types
The morphology 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.''In vivo'' – primate
The most common division of dendritic cells is conventional dendritic cells vs. plasmacytoid dendritic cell as described in the table below:| Name | Description | Secretion | Toll-like receptors |
| Conventional dendritic cell | Most similar to monocytes. mDC are made up of at least two subsets:
| Interleukin 12, Interleukin 6, TNF, chemokines | TLR 2, TLR 4 |
| Plasmacytoid dendritic cell | Look like plasma cells, but have certain characteristics similar to myeloid dendritic cells. | Can produce high amounts of interferon-α and were previously called interferon-producing cells. | TLR 7, TLR 9 |
File:Centrocyte, centroblast and follicular dendritic cell in a follicular lymphoma.jpg|thumb|Histologic comparison of cell types in a germinal center, including follicular dendritic cells, H&E stain:
- Centrocytes are small to medium size with angulated, elongated, cleaved, or twisted nuclei.
- Centroblasts are larger cells containing vesicular nuclei with one to three basophilic nucleoli apposing the nuclear membrane.
- Follicular dendritic cells have round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane.
Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors, respectively, and thus are of hematopoietic origin. By contrast, follicular dendritic cells are probably of mesenchymal rather than hematopoietic origin and do not express MHC class II, but are so named because they are located in lymphoid follicles and have long "dendritic" processes.
In blood
The blood DCs are typically identified and enumerated in flow cytometry. Three types of DCs have been defined in human blood: the CD1c+ myeloid DCs, the CD141+ myeloid DCs and the CD303+ plasmacytoid DCs. This represents the nomenclature proposed by the nomenclature committee of the International Union of Immunological Societies.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, cross-presentation, and IFNalpha production.
''In vitro''
In some respects, dendritic cells cultured in vitro do not show the same behaviour or capability as dendritic cells isolated ex vivo. Nonetheless, they are often used for research as they are still much more readily available than genuine DCs.- Mo-DC or MDDC refers to cells matured from monocytes.
- HP-DC refers to cells derived from hematopoietic progenitor cells.
Development and life cycle
Formation of immature cells and their maturation
Dendritic cells are derived from hematopoietic bone marrow progenitor cells. 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 as viruses and bacteria. This is done through pattern recognition receptors such as the toll-like receptors. TLRs recognize specific chemical signatures found on subsets of pathogens. Immature dendritic cells may also phagocytose 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 a lymph node. Immature dendritic cells phagocytose pathogens and degrade their proteins into small pieces and upon maturation present those fragments at their cell surface using MHC molecules. Simultaneously, they upregulate cell-surface receptors that act as co-receptors in T-cell activation such as CD80, CD86, and CD40 greatly enhancing their ability to activate T-cells. They also upregulate CCR7, a chemotactic receptor that induces the dendritic cell to travel through the blood stream to the spleen or through the lymphatic system to a lymph node. Here they act as antigen-presenting cells: they activate helper T-cells and killer T-cells as well as B-cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals. Dendritic cells can also induce T-cell tolerance. Certain C-type lectin receptors 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.Every helper T-cell is specific to one particular antigen. Only professional antigen-presenting 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 activate memory T cells whereas dendritic cells can activate both memory and naive 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. This help from CD4+ T cells additionally activates the matured dendritic cells and licenses them to efficiently induce CD8+ memory T cells, which are also able to be expanded a second time. 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.
As mentioned above, mDC probably arise from monocytes, white blood cells which circulate in the body and, depending on the right signal, can turn into either dendritic cells or macrophages. The monocytes in turn are formed from stem cells in the bone marrow.
Monocyte-derived dendritic cells can be generated in vitro from peripheral blood mononuclear cell. Plating of PBMCs in a tissue culture flask permits adherence of monocytes. Treatment of these monocytes with interleukin 4 and granulocyte-macrophage colony stimulating factor leads to differentiation to immature dendritic cells in about a week. Subsequent treatment with tumor necrosis factor further differentiates the iDCs into mature dendritic cells. Monocytes can be induced to differentiate into dendritic cells by a self-peptide Ep1.B derived from apolipoprotein E. These are primarily tolerogenic plasmacytoid dendritic cells.
Life span
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.Research challenges
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 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.Cytokines
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 the B7 family of the dendritic cell with CD28 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-12. IL-12 is a signal that helps send naive CD4 T cells towards a Th1 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 of type-1 IFNs, which recruit more activated macrophages to allow phagocytosis.