Dendritic cells (DCs) are
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes usi ...
s (also known as ''accessory cells'') of the
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur ...
ian
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
. Their main function is to process
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
material and
present it on the cell surface to the
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s of the immune system. They act as messengers between the
innate and the
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
s.
Dendritic cells are present in those tissues that are in contact with the external environment, such as the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
(where there is a specialized dendritic cell type called the
Langerhans cell) and the inner lining of the
nose
A nose is a protuberance in vertebrates that houses the nostrils, or nares, which receive and expel air for respiration alongside the mouth. Behind the nose are the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passe ...
,
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either si ...
,
stomach and
intestine
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
s. They can also be found in an immature state in the
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
. Once activated, they migrate to the
lymph nodes where they interact with
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s 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 (δένδρον or déndron being Greek for 'tree'). While similar in appearance, these are structures distinct from the dendrites of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s. 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 (hence ''Langerhans cells'') in the late nineteenth century. The term ''dendritic cells'' was coined in 1973 by
Ralph M. Steinman
Ralph Marvin Steinman (January 14, 1943 – September 30, 2011) was a Canadian physician and medical researcher at Rockefeller University, who in 1973 discovered and named dendritic cells while working as a postdoctoral fellow in the labora ...
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
The Albert Lasker Award for Basic Medical Research is one of the prizes awarded by the Lasker Foundation for a fundamental discovery that opens up a new area of biomedical science. The award frequently precedes a Nobel Prize in Medicine; almost 5 ...
in 2007
and the
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
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 (a.k.a. myeloid dendritic cells) vs.
plasmacytoid dendritic cell (most likely of
lymphoid lineage) as described in the table below:
The markers
BDCA-2
CLEC4C is a membrane protein of plasmacytoid dendritic cells used as a marker for this kind of cells and denoted as CD303 in the nomenclature of the Cluster of differentiation
The cluster of differentiation (also known as cluster of designatio ...
,
BDCA-3, and
BDCA-4
Neuropilin is a protein receptor active in neurons.
There are two forms of Neuropilins, NRP-1 and NRP-2. Neuropilins are transmembrane glycoproteins, first documented to regulate neurogenesis and angiogenesis by complexing with Plexin rece ...
can be used to discriminate among the types.
Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors, respectively, and thus are of
hematopoietic origin. By contrast,
follicular dendritic cells (FDC) are probably of
mesenchymal rather than
hematopoietic origin and do not express
MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cell ...
, 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
The International Union of Immunological Societies (IUIS), a member of the International Council for Science, is an organization which serves as an umbrella organization for many national and regionally grouped immunological societies. The organi ...
.
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 Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present ''extracellular'' antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, th ...
(in CD141+ myeloid DCs), and IFNalpha production (in CD303+ plasmacytoid DCs).
''In vitro''
In some respects, dendritic cells cultured
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
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
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s.
* 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 (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 as
viruses and
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
. This is done through
pattern recognition receptors
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells o ...
(PRRs) such as the
toll-like receptors (TLRs). 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
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s 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 (B7.1),
CD86 (B7.2), and
CD40 greatly enhancing their ability to activate T-cells. They also upregulate
CCR7
C-C chemokine receptor type 7 is a protein that in humans is encoded by the ''CCR7'' gene. Two ligands have been identified for this receptor: the chemokines (C-C motif) ligand 19 (CCL19/ELC) and (C-C motif) ligand 21 (CCL21).
CCR7 has also rece ...
, a chemotactic receptor that induces the dendritic cell to travel through the
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
stream to the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . or through the
lymphatic system to a
lymph node. Here they act as
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes usi ...
s: 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 (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.
Every helper T-cell is specific to one particular antigen. Only professional
antigen-presenting cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes usin ...
(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 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
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
.
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.
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
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s, white blood cells which circulate in the body and, depending on the right signal, can turn into either dendritic cells or
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s. 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
A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes ( T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes ...
(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 from
apolipoprotein E
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
. 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
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provi ...
present on the
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...
. However, the
cell–cell interaction can also take place at a distance via
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s.
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
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ce ...
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.
Disease
Blastic plasmacytoid dendritic cell neoplasm
Blastic plasmacytoid dendritic cell neoplasm is a rare type of
myeloid 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.
This presentation may be accompanied by cPC infiltrations into other tissues to result in swollen
lymph nodes, enlarged liver, enlarged spleen, symptoms of
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
dysfunction, and similar abnormalities in breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, and/or testes.
The disease may also present as a pDC
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
, i.e. increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) and bone marrow and evidence (i.e.
cytopenia
Cytopenia is a reduction in the number of mature blood cells. It is common in cancer patients being treated with radiation and/or chemotherapy.
Types
Anemia – a reduction of the red blood cells in the body.
Leukopenia – a deficiency of whit ...
s) of
bone marrow failure.
Blastic plasmacytoid dendritic cell neoplasm has a high rate of recurrence following initial treatments with various
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
regimens. In consequence, the disease has a poor overall prognosis and newer
chemotherapeutic
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
and novel
non-chemotherapeutic drug regimens to improve the situation are under study.
Viral infection
HIV, which causes
AIDS, can bind to dendritic cells via various receptors expressed on the cell. The best studied example is
DC-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). When the dendritic cell takes up HIV and then travels to the lymph node, the virus can be transferred to helper CD4+ T-cells, contributing to the developing infection. This infection of dendritic cells by HIV explains one mechanism by which the virus could persist after prolonged
HAART.
Many other viruses, such as the
SARS virus, seem to use DC-SIGN to 'hitchhike' to its target cells. 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.
Cancer
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.
Lung cancers have been found to include four different subsets of dendritic cells: three classical dendritic cell subsets and one plasmacytoid dendritic cell subset.
At least some of these dendritic cell subsets can activate CD4+ helper T cells and
CD8+ cytotoxic T cells, which are immune cells that can also suppress
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
growth. 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.
Autoimmunity
Altered function of dendritic cells is also known to play a major or even key role in
allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
and
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s like
lupus erythematosus and inflammatory bowel diseases (
Crohn's disease and
ulcerative colitis).
Other animals
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.
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.
Dendritic cells have been found in rainbow trout (''Oncorhynchus mykiss'') and zebrafish (''Danio rerio'') but their role is still not fully understood
[Salinas, I., & Parra, D. (2015). Fish mucosal immunity: Intestine. In Mucosal Health in Aquaculture. Elsevier Inc. https://doi.org/10.1016/B978-0-12-417186-2.00006-6]
Media
Image:Dendritic cell.JPG, A dendritic cell
Image:S8-Dendritic Cells Dragging Conidia in Collagen.ogg, A well-resolved dendritic cell drags a conidium through a distance of up to 9 μm. The conidium, however, is not phagocytosed by the cell. The observation was made over 3 h with one frame every 30 s.
Image:S6-Dendritic Cells with Conidia in Collagen.ogv, A single dendritic cell can be seen here efficiently taking up at least four conidia in its vicinity.
See also
*
Histiocyte
*
Macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
*
List of human clusters of differentiation
The following is a list of human clusters of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigati ...
for a list of CD molecules (such as
CD80 and
CD86)
References
External links
Website of the Center for Infection and Immunity of Lille contains information on DCs and their study in research, link currently dead
*
www.dc2007.eu 5th International Meeting on Dendritic Cell Vaccination and other Strategies to tip the Balance of the Immune SystemWebsite of Ralph M. Steinman at The Rockefeller Universitycontains information on DCs, links to articles, pictures and videos
"Cancer 'danger receptor' found" BBC News
BBC News is an operational business division of the British Broadcasting Corporation (BBC) responsible for the gathering and broadcasting of news and current affairs in the UK and around the world. The department is the world's largest broadc ...
, 15 February 2009
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Antigen presenting cells
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Human cells
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Mononuclear phagocytes