They are antigen presenting cells of the mammalian immune system.
Also known as accessory cells , their 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 immune system and the adaptive system.
Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a type of specialized dendritic cell called a Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. .
They can also be found in an immature 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 stages of development, branching projections grow, the dendrites that give the cell its name, although similar in appearance, these are structures distinct from the dendrites of neurons.
Immature dendritic cells are also called veiled cells, as they have large cytoplasmic “veils” instead of dendrites.
The morphology of the 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 total volume of the cell.
In vivo – primate
The most common division of dendritic cells is myeloid versus lymphoid .
Myeloid dendritic cell: the closest thing to monocytes. They are made up of at least two subsets:
- The most common mDC-1, which is a major stimulator of T cells.
- The extremely rare mDC-2, which may have a role in fighting wound infection.
Lymphoid dendritic cell: They look like plasma cells, but have certain characteristics similar to myeloid dendritic cells.
Lymphoid and myeloid dendritic cells evolve from lymphoid and myeloid precursors, respectively, and are therefore of hematopoietic origin.
In 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 found in lymphoid follicles and have long “dendritic” processes.
Dendritic blood cells are typically identified and enumerated on flow cytometry. Three types of dendritic cells have been defined in human blood:
- CD1c + myeloid dendritic cells.
- CD141 + myeloid dendritic cells.
- CD303 + plasmacytoid dendritic cells.
This represents the nomenclature proposed by the nomenclature committee of the International Union of Immune Societies.
Dendritic cells circulating in the blood do not have all the typical characteristics of their counterparts in tissue, that is, they are less mature and do not have dendrites.
Still, they can perform complex functions, including chemokine production (in CD1c + myeloid DC), cross-presentation (in CD141 + myeloid DC), and IFNalpha production (in CD303 + plasmacytoid DC).
In some aspects, dendritic cells grown in vitro do not show the same behavior or capacity as dendritic cells isolated ex vivo.
However, they are often used for research, as they are still much more widely available than genuine CDs.
- Mo-DC or MDDC refers to mature monocyte cells.
- HP-DC refers to cells derived from hematopoietic progenitor cells.
While humans and non-human primates, such as rhesus macaques, appear to have DC divided into these groups, other species (such as the mouse) have different subdivisions of DC.
Immature cell formation and 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 (PRRs), such as toll-type receptors. These receptors recognize specific chemical signatures found in subsets of pathogens.
Immature dendritic cells can also engulf small amounts of living cell membrane, in a process called nibbling. Once they have come into contact with a presentable antigen, they become activated in mature dendritic cells and begin to migrate to the lymph node.
Immature dendritic cells engulf pathogens and degrade their proteins into small fragments and, upon maturation, present these fragments on their cell surface using MHC molecules.
Simultaneously, they positively regulate cell surface receptors that act as coreceptors in T cell activation such as CD80 (B7.1), CD86 (B7.2), and CD40 greatly enhancing their ability to activate T cells.
They also positively regulate CCR7, a chemotactic receptor that induces the dendritic cell to travel through the bloodstream to the spleen or through the lymphatic system to a lymph node.
Here they act as antigen-presenting cells: T helper cells and killer T cells are activated, as well as B cells presenting them with pathogen-derived antigens, along with non-antigen-specific costimulatory signals.
Dendritic cells can also induce T cell tolerance (lack of response).
Certain C-type lectin receptors (CLRs) on the surface of dendritic cells, some function as PRRs, help instruct dendritic cells on when it is appropriate to induce immune tolerance rather than lymphocyte activation.
Each helper T cell is specific for a particular antigen. Only professional antigen-presenting cells (macrophages, B lymphocytes, and dendritic cells) can activate a resting helper T cell when the corresponding 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 T cells and the most potent of all antigen-presenting cells.
In the lymph node and secondary lymphoid organs, all three cell types can activate naïve T cells.
While mature dendritic cells are capable of activating 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 further activates mature dendritic cells and leaves them to efficiently induce CD8 + memory T cells, which can also expand a second time.
For this activation of dendritic cells, the simultaneous interaction of all three cell types, namely CD4 + T helper cells, CD8 + T cells and dendritic cells, appears to be necessary.
As mentioned above, DCMs likely arise from monocytes, white blood cells that circulate in the body and, depending on the correct signal, can develop into dendritic cells or macrophages.
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 cells (PBMC).
Plating PBMC in a tissue culture flask allows for the adherence of monocytes.
Treatment of these monocytes with interleukin 4 (IL-4) and granulocyte macrophage colony stimulating factor (GM-CSF) leads to differentiation into immature dendritic cells (CDIs) in approximately one week.
Subsequent treatment with tumor necrosis factor (TNF) further differentiates iDCs in mature dendritic cells. Monocytes can be induced to differentiate into dendritic cells by an ep1.B auto-peptide derived from apolipoprotein E.
These are mainly tolerogenic plasmacytoid dendritic cells.
Activated macrophages have a lifespan of only a few days, although new evidence suggests that it could extend to weeks rather than days.
The lifespan of activated dendritic cells, while varying somewhat by type and origin, is of a similar order of magnitude, but immature dendritic cells appear to be capable of existing in an inactivated state for much longer.
The exact genesis and development of the different types and subsets of dendritic cells and their interrelationship is only marginally understood at this time, as dendritic cells are so rare and difficult to isolate that it is only in recent years that they have become subjects of investigation.
Different surface antigens that characterize dendritic cells have been known since 2000; Before that, researchers had to work with a “cocktail” of various antigens that, combined, resulted in the isolation of cells with characteristics unique to DCs.
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 dendritic cell B7 family with CD28 present on the lymphocyte.
However, cell-cell interaction can also take place remotely via cytokines.
For example, stimulation of dendritic cells in vivo with microbial extracts causes dendritic cells to rapidly begin to produce IL-12. IL-12 is a signal that helps send naive CD4 T cells toward a Th1 phenotype.
The final consequence is the sensitization and activation of the immune system to attack the antigens that the dendritic cell presents on its surface. However, there are differences in the cytokines produced depending on the type of dendritic cell.
Plasmacytoid DC has the ability to produce large amounts of type 1 IFNs, which recruit more activated macrophages to allow phagocytosis.
HIV, which causes AIDS, can bind to dendritic cells through various receptors expressed on the cell.
The best-studied example is DC-SIGN (usually in the MDC 1 subset, but also in other subsets under certain conditions, as not all dendritic cell subsets express DC-SIGN, its exact role in the sexual transmission of HIV-1 not clear).
When the dendritic cell takes on HIV and then travels to the lymph node, the virus can transfer to CD4 + helper cells, contributing to the development of infection. This HIV infection of dendritic cells explains a mechanism by which the virus might persist after prolonged HAART.
Many other viruses, such as the SARS virus, appear to use DC-SIGN to ‘hitchhike’ their target cells. However, most of the work with binding of viruses to cells expressing DC-SIGN has been carried out using in vitro derived cells such as moDCs. The physiological function of DC-SIGN in vivo is more difficult to determine.
Altered dendritic cell function is also known to play a major or even key role in allergies and autoimmune diseases such as lupus erythematosus and inflammatory bowel diseases ( Crohn’s disease and ulcerative colitis ).