Dendritic cell
Encyclopedia
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells
Antigen-presenting cell
An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...
. They act as messengers between the innate
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
and adaptive immunity
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
.
Dendritic cells are present in tissues in contact with the external environment, such as the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
(where there is a specialized dendritic cell type called Langerhans cells
Langerhans cell
Langerhans cells are dendritic cells of the skin and mucosa, and contain large granules called Birbeck granules. They are present in all layers of the epidermis, but are most prominant in the stratum spinosum. They also occur in the papillary dermis, particularly around blood vessels, as well as...
) and the inner lining of the nose
Human nose
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils...
, lungs, stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
and intestines
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. They can also be found in an immature state in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
. Once activated, they migrate to the lymph nodes
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
where they interact with T cells
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
and B cells
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites
Dendrite (non-neuronal)
A dendrite is a branching projection of the cytoplasm of a cell. While the term is most commonly used to refer to the branching projections of neurons, it can also be used to refer to features of other types of cells that, while having a similar appearance, are actually quite distinct...
that give the cell its name (δένδρον or déndron being Greek for "tree"). While similar in appearance, these are distinct structures from the dendrites of neurons
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
. 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 LangerhansPaul Langerhans
Paul Langerhans was a German pathologist, physiologist and biologist.-Eponymous terms:* Islets of Langerhans - Pancreatic cells which produce insulin...
(Langerhans cells) in the late nineteenth century. It wasn't until 1973, however, that the term "dendritic cells" was coined by Ralph M. Steinman
Ralph M. Steinman
Ralph Marvin Steinman was a Canadian immunologist and cell biologist at Rockefeller University, who in 1973 coined the term dendritic cells while working as a postdoc in the lab of Zanvil A. Cohn, also at Rockefeller University....
and Zanvil A. Cohn
Zanvil A. Cohn
Zanvil Alexander Cohn a cell biologist and immunologist was a professor at Rockefeller University. There Cohn had been the Henry G. Kunkel Professor for seven years. Cohn was senior physician at the university as well as vice president for medical affairs...
. For discovering the central role of dendritic cells in the adaptive immune response, Steinman was awarded the Albert Lasker Award for Basic Medical Research
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 the understanding, diagnosis, prevention, treatment, and cure of disease...
in 2007 and the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 2011.
Types of dendritic cells
In all dendritic cells, the similar morphology results in a very large contact surface to their surroundings compared to overall cell volume.In vivo - primate
The most common division of dendritic cells is "myeloidMyeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
" vs. "plasmacytoid":
| Name | Description | Secretion | Toll-like receptors Toll-like receptor Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes... >- | Myeloid dendritic cell (mDC) |
Most similar to monocytes Monocyte Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function... . mDC are made up of at least two subsets: (1) the more common mDC-1, which is a major stimulator of T cells (2) the extremely rare mDC-2, which may have a function in fighting wound infection |
IL-12 Interleukin 12 Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:... |
TLR 2 TLR 2 Toll-like receptor 2 also known as TLR-2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282 . TLR-2 plays a role in the immune system... , TLR 4 TLR 4 Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR 4 is a toll-like receptor. It detects lipopolysaccharide from Gram-negative bacteria and is thus important in the activation of the innate immune system... >- | Plasmacytoid dendritic cell Plasmacytoid dendritic cell Plasmacytoid dendritic cells are innate immune cells that circulate in the blood and are found in peripheral lymphoid organs. They constitute... (pDC) |
Look like plasma cells Plasma cell Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system... , but have certain characteristics similar to myeloid dendritic cells. |
Can produce high amounts of interferon-alpha Interferon Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to... and thus became known as IPC (interferon-producing cells) before their dendritic cell nature was revealed. |
TLR 7 TLR 7 Toll-like receptor 7, also known as TLR7, is protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.- Function :... , TLR 9 |
The markers BDCA-2, BDCA-3, and BDCA-4 can be used to discriminate among the types.
Lymphoid and myeloid DCs evolve from lymphoid or myeloid precursors respectively and thus are of hematopoietic origin. By contrast, follicular dendritic cells
Follicular dendritic cells
Follicular dendritic cells are cells of the immune system found in lymph follicles of secondary lymphoid organs and tertiary lymphoid organs. They are probably not of hematopoietic origin, though they look similar to true dendritic cells due to their filiform dendritic processes, but are of...
(FDC) are probably of mesenchymal rather than hematopoietic origin and do not express MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
, but are so named because they are located in lymphoid follicles and have long "dendritic" processes.
In vitro
In some respects, dendritic cells cultured in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
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 monocytesMonocyteMonocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
- HP-DC refers to cells derived from hematopoietic progenitor cellsPluripotential hemopoietic stem cellHematopoietic stem cells , also spelled Hæmatopoietic stem cells, are multipotent stem cells that give rise to all the blood cell types from the myeloid , and lymphoid lineages...
.
Nonprimate
While humans and non-human primates such as Rhesus macaquesRhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
appear to have DCs divided into these groups, other species (such as the mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
) have different subdivisions of DCs.
Formation of immature cells
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 bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. This is done through pattern recognition receptors (PRRs) such as the toll-like receptors
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
(TLRs). TLRs recognize specific chemical signatures found on subsets of pathogens. Immature dendritic cells may also phagocyte 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 the lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
. Immature dendritic cells phagocytose pathogens and degrade their proteins
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
into small pieces and upon maturation present those fragments at their cell surface using MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules. Simultaneously, they upregulate cell-surface receptors that act as co-receptors in T-cell activation such as CD80
CD80
Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
(B7.1), CD86
CD86
Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival...
(B7.2), 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
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream to the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
or through the lymphatic system
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
to a lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
. Here they act as antigen-presenting cells
Antigen-presenting cell
An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...
: 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.
Every helper T-cell is specific to one particular antigen. Only professional antigen-presenting cells (macrophages, B lymphocytes, and dendritic cells) are able to activate a resting helper T-cell when the matching antigen is presented. However, macrophages and B cells can only activate memory T cells
Memory T cells
Memory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...
whereas dendritic cells can activate both memory and naive T cells, and are the most potent of all the antigen-presenting cells.
As mentioned above, mDC probably arise from monocytes
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
, white blood cells which circulate in the body and, depending on the right signal, can turn into either dendritic cells or macrophages
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
. The monocytes in turn are formed from stem cells in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
.
Monocyte-derived dendritic cells can be generated in vitro from peripheral blood mononuclear cells (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.
Life span of dendritic cells
Activated macrophages have a lifespan of only a few days though new evidence suggest that it could be extended to weeks rather than days. The lifespan of activated dendritic cells, while somewhat varying according to type and origin, is of a similar order of magnitude, but immature dendritic cells seem to be able to exist in an inactivated state for much longer.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.Dendritic cells and cytokines
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the membrane proteins of the B7B7 (protein)
B7 is a type of peripheral membrane protein found on activated antigen presenting cells that, when paired with either a CD28 or CD152 surface protein on a T cell, can produce a costimulatory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively...
family of the dendritic cell with CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
present on the lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
. However, the cell–cell interaction can also take place at a distance via cytokines
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
.
For example, stimulating dendritic cells in vivo with microbial extracts causes the dendritic cells to rapidly begin producing IL-12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
. IL-12 is a signal that helps send naive CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
T cells towards a Th1
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
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 lymphoid DC has the ability to produce huge amounts of type-1 IFN's, which recruit more activated macrophages to allow phagocytosis.
HIV infection
HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, which causes AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, can bind to dendritic cells via various receptors expressed on the cell. The best studied example is DC-SIGN
DC-SIGN
DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene....
(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
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
. Many other viruses, such as the SARS virus seems 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.
Autoimmunity
Altered function of dendritic cells is also known to play a major or even key role in allergyAllergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
and autoimmune diseases
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
like lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
and inflammatory bowel diseases (Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
and ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
).
Dendritic cells in animals other than humans
The above applies to humans. In other organisms, the function of dendritic cells can differ slightly. For example, in brown ratsBrown Rat
The brown rat, common rat, sewer rat, Hanover rat, Norway rat, Brown Norway rat, Norwegian rat, or wharf rat is one of the best known and most common rats....
(but not mice), a subset of dendritic cells exists that displays pronounced killer cell-like activity, apparently through its entire lifespan. 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.
Although typically described in mammals, dendritic cells have also been found in chickens and turtles.
See also
- Active Hexose Correlated CompoundActive Hexose Correlated CompoundActive Hexose Correlated Compound is an alpha-glucan rich nutritional supplement produced from the mycelia of shiitake of the basidiomycete family of mushrooms, and is not an approved drug. AHCC was originally designed to lower high-blood pressure...
- List of human clusters of differentiation for a list of CD molecules (such as CD80CD80Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
and CD86CD86Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival...
)
External links
- www.dc2007.eu : 5th International Meeting on Dendritic Cell Vaccination and other Strategies to tip the Balance of the Immune System
- Website of Dr. Ralph M. Steinman at The Rockefeller University contains information on DCs, links to articles, pictures and videos
- Cancer 'danger receptor' found, BBC News, 15 February 2009