Dendritic Cells

Definition, Production, Function and Immunology



Derived from precursors in the bone marrow, Dendritic cells (DC) are professional antigen-presenting cells typically found in the mucosa, skin, and lymphoid tissues. As antigen-presenting cells, these cells are primarily involved in processing antigen before presenting them to T cells in order to activate immune response. 

While dendritic cells play a central role in the activation of naive T cells and associated immunological responses, they also promote immune tolerance towards self-antigens thus preventing the occurrence of autoimmune disease. 



In human beings and other animals, a variety of dendritic cells have been identified and classified into the following categories:

 

  • Conventional dendritic cells (cDCs)
  • Plasmacytoid dendritic cells (pDCs)
  • Monocyte-derived dendritic cells - Often used in cancer immunotherapy 

 

* The name dendritic cells is due to the fact that these cells have long branches/extensions resembling those of dendrites (extensions of nerve cells).

 


Production of Dendritic Cells


According to studies that were aimed at observing the production of dendritic cells in mice, researchers noticed that with the exception of Langerhans cells (a type of dendritic cells commonly found in epidermal layers and various epithelia) dendritic cells originate from precursors (monocyte-dendritic cell precursors) found in the bone marrow.

These cells, also known as macrophage-dendritic cell precursors divide to produce the common monocyte progenitors as well as common dendritic cell progenitors (cDPs) with the common dendritic progenitors ultimately giving rise to pre-dendritic cells and plasmacytoid dendritic cells. In turn, these cells migrate to the lymphoid (as well as non-lymphoid) tissues where they differentiate for produce subsets of the classical dendritic cells. 

In human beings, the hematopoietic stem cells located in the bone marrow have been shown to first differentiate into multi-lymphoid progenitors and granulocyte-macrophage progenitor cells before giving rise to the human equivalent of macrophage-dendritic cell progenitors (or common dendritic cell progenitors).

In turn, the MDP-like progenitor (or CDP-like progenitors) differentiates to produce the plasmacytoid dendritic cell and pre-dendritic cells that ultimately give rise to plasmacytoid dendritic cells and classical dendritic cells respectively.

The MDP or CDP-like progenitors also produce common monocyte progenitor that differentiates to form monocytes that ultimately give rise to inflammatory monocyte-derived dendritic cells. 

* As compared to the other dendritic cells, Langerhans cells are produced by the precursor cells that reside in the yolk sac or fetal liver.


The different subtypes of dendritic cells (e.g. Langerhans cells, Plasmacytoid DC, Interdigitating DC, and Myeloid DC) not only have different origins, but also different receptors and varying functions.

Because of their heterogeneous nature with regards to phenotype, location within the body, as well as their respective immunological functions, they are well able to stimulate appropriate immune responses when exposed to different types of invading pathogens. 



Plasmacytoid Dendritic Cells (pDC)



Plasmacytoid dendritic cells are a subset of dendritic cells that release Type I interferons in the presence of viral and bacterial pathogens. This being one of their main characteristics, they have been described as professional Type I interferon producing cells in some books.

By producing cytokines and their role in Ag presentation, plasmacytoid dendritic cells link the innate and adaptive immune system making important contributors to the immune system as a whole. 

Like classical/conventional dendritic cells, plasmacytoid dendritic cells originate from hematopoietic stem cells located in the bone marrow and makeup about 0.05 percent of the total peripheral blood mononuclear cells.

With regards to morphology, they are medium-sized with an average diameter between that of lymphocytes and monocytes. They contain a rounded/ovoid nucleus which may appear slightly indented when viewed under the microscope.


Some of the other cell characteristics of plasmacytoid dendritic cells include:

  • Reticular/finely dispersed chromatin
  • Eosinophilic cytoplasm
  • Poorly visible nucleoli


Production of IFN-1

While a number of other cells are capable of producing type I interferon, it is the unique molecular adaptation of plasmacytoid dendritic cells that have won them the term "professional type I interferon producing cells". As a result of this unique property, they are well suited to sense foreign nucleic acids and consequently produce large amounts of the interferon. 

For this reason, in the body,  plasmacytoid dendritic cells serve to recognize various pathogen-associated molecular patterns (PAMPs) (e.g. viral single-strand RNA, CpG nucleotide DNA sequences of bacteria, peptidoglycans, and lipopolysaccharides, etc) which stimulates them to secrete and release such signals as interleukin-6 and type I interferons in response to the infection.

Here, presence of the pathogen stimulates the TLR8-MyD88-IRF7 pathway which in turn stimulates the production of type I interferon by plasmacytoid dendritic cells.

* The transcription of type I interferon is regulated by a number of interferon-regulating factors such as IRF- 3 and 7 as well as transcription factor NF-kB.


* pDCs can produce type I interferons between 100 and 1000 times more than other blood cells.

Once the proteins (type I interferons) are released, they directly activate various activities of both the innate and adaptive immunity in response to the invading pathogen. For instance, IFN- α and β activate hey cytotoxic and phagocytic activities of macrophages, the ability of classical dendritic cells to present antigens, the production of proinflammatory cytokines, and TNF-α, etc. 

Through these mechanisms, both the innate and adaptive immune systems are activated to respond to given invading pathogens and effectively destroy them.


Some of the other functions of type I interferons in the immune system include:

· Up-regulate the production of IFN-y by natural killers cells and T cells. Here, IFN-y, which have antiviral properties act against viral pathogens


· Inhibit the replication of viruses as well as bacterial proliferation in the body 

 

By binding to the IFN-α and IFN-β receptors located on the surface of pDCs, IFN-1 also stimulates a positive feedback autocrine response. 

Apart from type I interferon, plasmacytoid dendritic cells also produce interleukin 6 and tumor necrosis factor-α that not only activates the classical dendritic cells, but also activates the differentiation of B cells into antibody-producing cells.

By activating the markers located on T cells, type I interferons have also been shown to promote the long-term antitumor response to counter the development of tumorous cells.

Tolerogenic properties - pDCs have been shown to present tolerogenic properties in a number of ways. For instance, whereas thymic pDCs promote Treg (regulatory T cells) those located in the liver and airways control oral and mucosal tolerance. 



As Antigen-Presenting Cells


While this is not their primary function, pDCs have also been shown to act as antigen-presenting cells. Following inflammation, large numbers of these cells are recruited to the infected/inflamed tissue, draining lymph nodes as well as lymph nodes where T cells are located.

Here, pDCs activate the T cells by attaching to, processing and presenting antigens with the use of MHCI and MHCII molecules. As immature cells, pDC are unable to effectively promote the proliferation of T cells. According to a number of studies, they have also been shown to suppress regulatory T cells. 

* Here, it's worth noting that the antigen-presenting ability of pDCs has only been demonstrated in vitro. For this reason, more studies are required to determine without a doubt whether this occurs in vivo.



HIV and Autoimmune Diseases in Human Beings

For instance, while they are involved in reduced viral spread during the early stages of HIV infection, continued production of IFN during later stages of viral replication has been shown to promote hyperactivation of polyclonal T cells and the consequent depletion of these cells (pDCs). 

In the case of HIV infections, the role of pDCs has been suggested to switch from protective to pathogenic. For instance, while they are involved in reduced viral spread during the early stages of HIV infection, continued production of IFN during later stages of viral replication has been shown to promote hyperactivation of polyclonal T cells and the consequent depletion of these cells (pDCs). 

As the infection continues, pDCs gradually lose their functionality and become depleted which directly contributes to immunodeficiency. Apart from contributing to immunodeficiency, pDCs have also been associated with autoimmune diseases in human beings.

In the case of such diseases like psoriasis and systemic lupus erythematosus, the high level of IFN produced by pDCs cells was shown to contribute to autoimmunity. 


Conventional Dendritic Cells (cDCs)


Also known as classical dendritic cells (or myeloid dendritic cells), conventional dendritic cells are all the different types of dendritic cells other than plasmacytoid dendritic cells. Because they reside in tissue, conventional dendritic cells are well-positioned to identify various exogenous and endogenous antigens and activate the appropriate immunological responses. 

Like some of the other cells of the immune system, classical/conventional dendritic cells are short-lived. However, they are regularly replenished by classical dendritic cell precursors that circulate in blood.  Currently, conventional dendritic cells are divided into two main categories. These include immature and mature dendritic cells. 

In the body, immature dendritic cells (which differentiate from monocytes) can be found in the peripheral tissues. Here, they engulf different types of pathogen/antigens through a process known as nonselective actin-mediated phagocytosis.

Once ingested, the antigens/pathogen are then broken down which allows dendritic cells (immature dendritic cells) to process their antigenic material and present them. 

* Antigen material have to be coupled/attached to the major histocompatibility complex molecules to be presented on the cell surface.

The maturation of dendritic cells, on the other hand, is activated by PAMPs (pathogen-associated molecular patterns). Using such pattern recognition receptors as toll-like receptors (TLRs), dendritic cells are able to recognize PAMPs (signals of invading pathogens) which activate the maturation process. 

Once they mature, the dendritic cells migrate to the lymph nodes where T cells recognize the antigen presented on the surface of mature dendritic cells.

Through this interaction, naive T cells are also activated to produce helper T cells or cytotoxic T cells that migrate to the site of infection to destroy invading pathogen. 

* In the absence of inflammation and co-stimulation, antigen presentation to the immature DC does not stimulate an immune response. 


* As compared to mature dendritic cells, immature dendritic cells cannot directly activate the proliferation of T cells. This is largely due to the fact that they do not produce sufficient cytokines required for this to be achieved.


Characterisitic of Mature and Immature Dendritic Cells


Based on microscopic studies, a number of morphological differences have been identified between mature and immature dendritic cells that contribute to the differences in their respective functions.

In comparison to mature DCs that have a rough surface (projections similar to those of dendrites), immature DCs have a round and smooth surface. 

Because of these differences, mature dendritic cells, using extensions on their surface, are well adapted for movement from one site to another. This characteristic allows them to migrate and activate naive T cells. Immature cells are well suited for phagocytosis, a process that allows them to process antigen material. 

Apart from difference in morphology, there are also differences in the types of molecules produced. Because immature dendritic cells produce low levels of co-stimulatory molecules (e.g. CD83) as well as limited amounts of immunostimulatory cytokines, they are unable directly activate naive T cells.

However, because mature cells are capable of producing sufficient amounts of these molecules, they are able to activate naive T cells. 


* While it had proved challenging to describe different phenotypes of classical dendritic cells based on their surface markers, recent studies have found Zbtb46, a cDC specific antigen, to be more reliable for this. This is because the gene is expressed in the cDCs of both murine and human beings as well as their progenitors. 



Dendritic Cells in the Skin 


As members of dendritic family, Langerhans cells contribute to both innate and adaptive responses. In the skin, they are located in the epidermis where they form a dense network. This allows them to effectively interact with invading microorganisms from the external environment. 

Under normal circumstances, Langerhans cells activate regulatory T cells located in the skin thus inhibiting T cell actions. In the event of an infection, they stimulate innate antimicrobial responses as well as an adaptive response by activating components of T cells. 


Monocyte-Derived Dendritic Cells


While monocyte-derived dendritic cells were not regarded as dendritic cells by some, they, like pDCs, have been accepted as a subset of dendritic cells (nonclassical dendritic cells).

Based on findings from a number of previous studies, researchers concluded that for dendritic cells found in lymphoid organs and mucosal surfaces, differentiation did not occur in the bone marrow. One of the biggest pieces of evidence for this was the fact that the subpopulations of these dendritic cells could not be found in the bone marrow. 

According to the findings, it was evident that precursors of these populations were present in blood. In support, new studies found that in the event of an infection, monocytes can differentiate into dendritic cells. For this reason, monocyte-derived dendritic cells are also referred to as inflammatory dendritic cells (inflammatory DCs). 

Typically, monocytes differentiate into macrophages capable of ingesting and eliminating dead cells, foreign material and invading microorganisms etc. In special circumstances, under the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) during an infection, monocytes can differentiate into dendritic cells. 

* In blood and the bone marrow, monocytes are about 20 times more than dendritic cells.

Functions of Monocyte-Derived Dendritic Cells


Before they differentiate into dendritic cells, monocytes are first recruited to the site of infection by proteins known as monocyte chemoattractant proteins (MCPs). Using cognate receptors (CCR2) located on their surface, monocytes detect MCPs and migrate to the site of infection where they differentiate to form dendritic cells. 

As such, they act as precursors of antigen-presenting dendritic cells in the event of an inflammation. Once they differentiate into dendritic cells, the monocytes are capable of presenting antigens to both the naive T cells and memory T cells for immune response. 

* Phenotypically, it's not easy to differentiate between monocyte-derived dendritic cells (moDCs) and conventional dendritic cells (cDC) given that their expression patterns of MHCII, CDIIb, and CB11c are similar. However, because monocyte-derived dendritic cells express CD64, it helps to discern them from classical dendritic cells.



Applications of Dendritic Cells in Immunology


As previously mentioned, dendritic cells are the most potent antigen-presenting cells. Because of this property, they are able to activate both the induced both the innate and adaptive immune responses.

Apart from their ability to process and present antigens to T cells (to activation naive T cell), dendritic cells have also been shown to express various molecules that either activate some cells of the immune system or inhibit/limit such responses.

Due to these properties, dendritic cells are some of the most important cells of the immune system, acting as the bridge between innate and adaptive immune responses.

Because of the beneficial properties and advancements in medical research, researchers have been able to develop dendritic cell-based (DC-based) vaccines to try and treat a number of diseases. A good example of this are immunotherapies that have been developed to try and treat cancer.

Given that dendritic cells are able to activate immune responses, these forms of treatment are aimed at activating specific immune cells to target and destroy cancer cells. Using pegylated IFN-α, for instance, the primary aim is to influence tumor-specific immune cells to destroy malignant cells. 

Apart from immunotherapies aimed at treating such diseases as cancer, DC-based treatments are also being used to promote immune tolerance of allografts. Treatments based on tolerogenic dendritic cells are used to maintain immune tolerance and thus prevent tissue rejection. 



See also:  White Blood Cells main pageAgranulocytes and Mast Cells

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References


Cindy Audiger et al. (2018). The importance of dendritic cells in maintaining immune tolerance. ncbi. 

Ghada Mohammad Zaki Al-Ashmawy. (2018). Dendritic Cell Subsets, Maturation and Function. 

Haibin Li and Bingyi Shi. (2015). Tolerogenic dendritic cells and their applications in transplantation

Jorge Schettini and Pinku Mukherjee. (2008). Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity. 

Leslie Guéry and Stéphanie Hugues. (2013). Tolerogenic and Activatory Plasmacytoid Dendritic Cells in Autoimmunity. ncbi. 

Pawel Kalinski, Ravikumar Muthuswamy, and Julie Urban. (2019). Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies. 

Links 

https://www.frontiersin.org/articles/10.3389/fimmu.2019.00778/full

https://www.nature.com/articles/cr2016157

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160806/


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