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Dendritic Cells -  Markers, Activation & Subtypes

Dendritic Cells - Markers, Activation & Subtypes

Exploring the multifaceted role of dendritic cells in immune function and disease.

Key Takeaways

  1. DCs are professional antigen-presenting cells that capture, process, and present antigens.
  2. They activate T cells and regulate immune responses by producing cytokines.
  3. DC markers help distinguish them from other cells.
  4. Different DC subtypes exist, each with unique functions.
  5. DCs play a vital role in immune surveillance and maintaining self-tolerance.
  6. They are involved in autoimmune diseases and cancer, both as protective and harmful factors.
  7. DCs have a crucial role in the development and regulation of immune responses.

What is a Dendritic Cell?

Dendritic cells (DCs) are a type of immune cell that acts as a messenger between the innate and adaptive immune system. They are professional antigen presenting cells (Wikipedia Contributors, 2020). They are similar to macrophages in that they use PRRs to recognise pathogenic molecules called PAMPs on the interior or exterior of the microbe, and phagocytose these pathogens. They then present a small part of the microbe called an antigen to a subset of immune cells called T cells. This leads to the overall activation of the immune system and the specialised killing of distinct microbes (Vyas, 2012). They can capture, process and present antigens on the surface of their cell. DCs can recognise pathogens, tissue damage signals and tumour antigens.

They present these antigens with molecules called major histocompatibility complexes (MHC) which can be divided into MHC-1 and MHC-2. MHC-1 recognises internal pathogens, whereas MHC-2 recognises external pathogens (Vyas, 2012). Once they have processed the antigen through the specific pathway based on whether or not the pathogen infected the cell externally or internally, they present this antigen to T cells on their MHC receptors. Dendritic cells can be found in virtually any tissue, and can detect homeostatic imbalances and can secrete a variety of pro-inflammatory molecules and growth factors (Mellman, 2013).

Dendritic Cells

The Function of Dendritic Cells

Dendritic cells are a type of white blood cell that is responsible for identifying pathogens and initiating the immune response. These cells are found in all tissues of the body, but they are most abundant in the skin and mucous membranes. Dendritic cells play a crucial role in the immune response by capturing and presenting antigens to T-cells. They are also involved in the regulation of immune responses by producing cytokines. Cytokines are proteins that help to regulate the activity of other cells in the immune system.

Dendritic cells are able to recognize antigens through a process called antigen presentation. This process begins when a dendritic cell comes into contact with a pathogen. The dendritic cell will then internalize the pathogen and process the antigens. Once the antigens have been processed, they are presented on the surface of the dendritic cell in a complex with MHC molecules. The dendritic cell will then migrate to a lymph node where it will come into contact with T-cells. The T-cells will recognize the presented antigens and become activated. The dendritic cell will also produce cytokines that help to regulate the immune response.

Dendritic cells are an important part of the immune system, and they play a crucial role in the recognition and response to pathogens.

Dendritic Cell Markers

There are a number of dendritic cell markers that can be used to identify these cells, including classical dendritic cells and pre-plasmacytoid dendritic cells. Some of the most common markers for dendritic cells include CD1a, CD14, CD19, and CD209. These markers can be used to help distinguish dendritic cells from other cell types, and can be helpful in identifying dendritic cells in a variety of settings.

Because no particular cell marker has been discovered to be exclusively expressed on DCs, a variety of the presence and absence of various cell markers may be utilized to identify them. The table below lists critical markers that can be used in the identification of DCs, including their lack of lineage markers such as CD3 (T cell), CD14 (monocyte) CD19 (B cell), CD56 (NK cell) and CD66b (granulocyte).

Classical DC's - Human Classical DC's - Mouse pre-plasmacytoid DC's - Human pre-plasmacytoid DC's - Mou

BDCA-1

BCA-1

BDCA-2

BST-2

CD8

CD11b

BDCA-4

CD11cLow

CD8 alpha

CD11c

CD11cLow

Ly-6C

CD11b

CD24

CD45RA

Ly-49Q

CD11c

CD115

CD123

MHC Class IILow

CD103

CD117

ILT-7

TLR7

CD205

CD135

MHC Class IILow

TLR9

MHC Class II

Flt3

TLR7

MHC Class II

TLR9

Dendritic Cell Activation

Dendritic cells (DCs) are central players in the immune system, acting as sentinels that constantly monitor the body for potential threats. When they encounter a pathogen, DCs are activated and begin to produce cytokines, which help to orchestrate the immune response. One important cytokine produced by DCs is IL-12, which plays a key role in regulating the activity of DCs.

In an immune response, DCs are first activated by cytokines such as IL-1 and TNF-alpha. These cytokines stimulate the DCs to produce more IL-12. The increased levels of IL-12 then help to regulate the activity of DCs, keeping them in an active state so that they can continue to mount an effective immune response.

IL-12 is a key cytokine produced by dendritic cells (DCs) that helps to regulate their activity. In an immune response, DCs are first activated by cytokines such as IL-1 and TNF-alpha. These cytokines stimulate the DCs to produce more IL-12. The increased levels of IL-12 then help to regulate the activity of DCs, keeping them in an active state so that they can continue to mount an effective immune response.

IL-12 is a key cytokine that helps regulate dendritic cell (DC) activity. In an immune response, DCs are first activated by cytokines such as IL-1 and TNF-alpha. These cytokines stimulate the DCs to produce more IL-12. The increased levels of IL-12 then help to regulate the activity of DCs, keeping them in an active state so that they can continue to mount an effective immune response.

As dendritic cells are key regulators of the immune system, IL-12 plays an important role in maintaining dendritic cell activity and function. Therefore, IL-12 is essential for mounting an effective immune response against pathogens.

T-cell activation by dendritic cells

Dendritic cells are important cells in the immune system that help to activate T-cells. They produce cytokines such as TNF-alpha, IL-12p70, and IFN-gamma, which help to stimulate the activity of T-cells. This is important in order to keep the immune system functioning properly.

Cytokines produced by dendritic cells

Dendritic cells are important immune cells that play a central role in the initiation and regulation of immune responses. They are able to produce a variety of cytokines, which are signaling molecules that regulate various aspects of the immune response. Cytokines produced by dendritic cells can help to activate other immune cells, promote inflammation, and modulate the immune response.

Some of the cytokines that dendritic cells can produce include:

Cytokine Role

IL-12

IL-12 is a cytokine that plays an important role in the development of cell-mediated immunity. It can help to activate natural killer cells and T helper cells, and promote the production of interferon-gamma (IFN-gamma).

IL-23

IL-23 is a cytokine that is involved in the development and maintenance of cell-mediated immunity. It can help to activate dendritic cells, natural killer cells, and T helper cells.

Tumour Necrosis Factor (TNF)

TNF is a cytokine that has a variety of roles in the immune response. It can help to activate dendritic cells and promote inflammation.

Interferon gamma

IFN-gamma is a cytokine that plays a key role in the development and maintenance of cell-mediated immunity. It can help to activate dendritic cells, natural killer cells, and T helper cells.

Dendritic Cell Development

DC’s are found in two different states, mature and immature. When they are immature, they are not specialised and cannot recognise, process and present antigens to their respective cells. In order to become mature, their pattern recognition receptors (PRRs) need to be activated by various PAMPs. Additionally, the expression of receptors on their cell surface called co-stimulatory molecules need to be increased, in addition to chemokine receptors (Vyas, 2012).

DC’s are produced in the bone marrow and mature in the lymphoid and peripheral tissues until they are activated and migrate to the site of infection. The development of immature DCs to mature DCs requires the stimulation of several types of cytokines, chemokines and pathogen associated molecular patterns (PAMPS) (Hellman & Eriksson, 2007). Activation of DC’s can be recognised by MHC class II, B7-1/CD80, B7-2/CD86, CD40/TNFRS5 and CD83 expression. Additionally, dendritic cells secrete different cytokines based on the type of immune response that needs to be induced. For example, the production of TNF-alpha leads to the activation of the effector T cell, CD8+ T cell and Th1. Whereas, the production of IL-4 induces the activation of Th2 cells, and increased expression of TGF-beta stimulates the differentiation and activation of Treg cells (Nunez, 2001).

Additionally, in order for effective proliferation to occur, DC’s require the exposure to GM-CSF (granulocyte macrophage - colony stimulating factor) to activate and differentiate from their progenitor cell. Another growth factor important for DC differentiation is FLT3-L which can be measured using an ELISA kit to determine the level of DC activation and differentiation in a sample. Additionally, it has been noted that FLT3-L has a role in the development of DC’s in mucosal and lymphoid tissues (Hellman & Eriksson, 2007).

Dendritic Cell Subtypes

DCs can be subdivided into pDCs (plasmatoid DCs) and cDCs (classical DCs). cDCs are the more abundant subset found in the body and can be found in all tissues and in the circulatory system (Ueno et al., 2007). They express high levels of both MHC Class I and MHC Class II and are the conventional professional antigen-presenting cell.

The role of cDCs is to survey the host based on environmental stimuli that manifest in the form of phenotypic changes (Ueno et al., 2007). pDCs are a smaller subdivision of dendritic cells and are found circulating in the blood and lymphoid tissues and reside in the lymph nodes. They have a much lower expression level of MHC Class II and costimulatory molecules, however upon recognition of foreign nucleic acid, they produce huge amounts of type 1 interferon which allows them to present foreign antigens to T cells (Ueno et al., 2007).

Follicular Dendritic Cells

Follicular dendritic cells (FDCs) are a type of cell found in the lymph nodes, spleen, and mucosal-associated lymphoid tissue. FDCs play an important role in immunity by presenting antigens to B cells and helping to regulate the immune response. FDCs are unique in that they have the ability to capture and store antigens on their surface. This allows FDCs to present a wide variety of antigens to B cells, which helps to ensure that the immune response is effective against a wide range of pathogens.

FDCs are part of the adaptive immune system and are important in both humoral immunity (mediated by antibodies) and cell-mediated immunity (mediated by T cells). FDCs help to activate B cells and T cells, and they also play a role in the development of memory B cells and memory T cells.

FDCs are found in all lymphoid organs, but they are most abundant in the follicles of lymph nodes. FDCs are also found in the spleen and in mucosal-associated lymphoid tissue (MALT), such as the tonsils, Peyer's patches, and the appendix.

The role of follicular dendritic cells is to capture antigens and present them to B cells. FDCs have a unique ability to take up antigens and display them on their surface. This allows FDCs to present a wide variety of antigens to B cells, which helps to ensure that the immune response is effective against a wide range of pathogens.

FDCs are found in all lymphoid organs, but they are most abundant in the follicles of lymph nodes.

Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tDCs) are a type of dendritic cell that has the ability to induce tolerance in immune cells. tolerogenic dendritic cells can be found in the lymph nodes, thymus, and bone marrow. These cells play an important role in the maintenance of self-tolerance and the prevention of autoimmunity.

Tolerogenic dendritic cells can be induced by a variety of different stimuli, including cytokines, lipids, and small molecules. Once tolerogenic dendritic cells are activated, they secrete a number of immunosuppressive factors that help to dampen the immune response.

There are a number of different types of tolerogenic dendritic cells, each with their own unique set of tolerogenic factors. The most well-characterized type of tolerogenic dendritic cell is the tolerogenic plasmacytoid dendritic cell (tPDC). tPDCs are a subset of dendritic cells that produce high levels of the tolerogenic factor interleukin-10 (IL-10).

Other types of tolerogenic dendritic cells include tolerogenic myeloid dendritic cells (tMDCs) and tolerogenic natural killer cells (tNKs). tMDCs are a subset of dendritic cells that produce the tolerogenic factors interleukin-6 (IL-6) and transforming growth factor beta (TGFβ). tNKs are a type of natural killer cell that produces the tolerogenic factor interleukin-15 (IL-15).

The tolerogenic factors secreted by tolerogenic dendritic cells help to suppress the immune response and prevent autoimmunity. In addition, tolerogenic dendritic cells can also promote the generation of regulatory T cells (Tregs). Tregs are a type of immune cell that helps to keep the immune response in check and prevent autoimmunity.

Epidermal Dendritic Cells  

Epidermal dendritic cells (EDCs) are epidermal cells that play a role in antigen presentation and immune surveillance. They are found in the epidermis, the outermost layer of the skin, and are part of the innate immune system. EDCs have the ability to capture antigens from their environment and present them to T cells, which are a type of white blood cell that is involved in the adaptive immune response. This process helps the body to mount an effective immune response against potential threats.

EDCs are thought to be important in the development of autoimmune diseases such as psoriasis and eczema, as well as in the management of skin cancer. In people with psoriasis, EDCs are thought to contribute to the overproduction of skin cells, which leads to the formation of scaly, itchy patches on the skin. In people with eczema, EDCs are thought to be involved in the development of inflammation and itchiness. In skin cancer, EDCs are thought to play a role in the development of tumors.

EDCs are a type of antigen-presenting cell (APC). APCs are cells that play a role in the immune response by presenting antigens to T cells. Other types of APCs include macrophages, dendritic cells, and B cells.

Interdigitating Dendritic Cells

Interdigitating dendritic cells are a type of cell that is found in the lymph nodes and spleen. These cells play an important role in the immune system by helping to capture and process antigens. interdigitating dendritic cells are unique in that they have both antigen-presenting and immunoregulatory properties.

This makes them an important part of the immune system, as they are able to help regulate the response to antigens. interdigitating dendritic cells are also involved in the development of immunity, as they help to produce antibodies that can recognize and destroy foreign invaders. interdigitating dendritic cells are a critical part of the immune system and play a vital role in protecting the body from disease.

Dendritic Cells and Cancer

Blastic Plasmacytoid Dendritic Cell Neoplasm  

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive type of cancer that starts in the dendritic cells. These cells are part of the immune system and help to fight infection.

BPDCN is most commonly diagnosed in older adults, with an average age at diagnosis of 68 years. It is more common in men than women, and tends to be more aggressive in men than women.

The cause of BPDCN is unknown. However, it is thought to be related to a change (mutation) in the genes that control the growth and division of dendritic cells. This gene mutation may be acquired (acquired mutation) or inherited (inherited mutation).

The most common symptom of BPDCN is skin lesions. These may be raised and red, or flat and purple. They can occur anywhere on the body, but are most commonly found on the trunk (chest and back), head, and neck. Other symptoms include fatigue, fever, weight loss, and bone pain.

BPDCN is usually diagnosed with a biopsy of the skin lesion. The biopsy sample is then examined under a microscope to look for abnormal dendritic cells. Additional tests, such as blood tests, bone marrow biopsy, and imaging tests, may also be done to confirm the diagnosis and stage the disease.

Treatment for BPDCN typically involves a combination of chemotherapy and immunotherapy. The specific drugs and doses used will depend on the individual patient. Clinical trials are ongoing to test new treatments for BPDCN.

Patients with BPDCN may have a high risk of recurrence (the cancer comes back). It is important to follow up with your healthcare team after treatment to monitor for recurrence.

Follicular Dendritic Cell Sarcoma

Follicular dendritic cell sarcoma is a type of cancer that arises from follicular dendritic cells. These are a type of cell that is found in the lymph nodes and helps to trap antigens. Follicular dendritic cell sarcomas are very rare, and often occur in the head and neck region. They can also occur in other parts of the body, such as the skin, gastrointestinal tract, and reproductive organs. Treatment for follicular dendritic cell sarcoma typically involves surgery and/or radiation therapy. Chemotherapy may also be used in some cases. Prognosis for follicular dendritic cell sarcoma is generally good, but can vary depending on the tumor's size and location.

Refrences

  • Hellman, P., and Eriksson, H. (2007) Early activation markers of human peripheral dendritic cells. Hum Immunol 68: 324-     333.
  • Mellman, I. (2013) Dendritic cells: master regulators of the immune response. Cancer Immunol Res 1: 145-149.
  • Nunez, R. (2001) Assessment of surface markers and functionality of dendritic cells (DCs). Curr Protoc Cytom Chapter 9:   Unit 9.17.
  • Vyas, J.M., (2012) The dendritic cell: the general of the army. In: Virulence. United States, pp. 601-602.
  • Wikipedia Contributors, W., (2020) Dendritic Cell.

Written by Pragna Krishnapur

Pragna Krishnapur completed her bachelor degree in Biotechnology Engineering in Visvesvaraya Technological University before completing her masters in Biotechnology at University College Dublin.

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12th Jun 2023 Pragna Krishnapur, MSc

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