- Dendritic cells (DCs) are antigen-presenting cells generated from progenitors in bone marrow and are widely dispersed throughout the body.
- DCs perform immune-surveillance for external and endogenous antigens and the subsequent activation of naive T cells, which results in a variety of immune responses. Different growth factors and cytokines, including GM-CSF, M-CSF, Flt3, and TGF-, can affect the differentiation and function of DCs, resulting in a wide range of DCs with distinct functional capabilities.
- Thus, DCs are categorised as plasmacytoid DCs (pDCs), conventional DCs (cDCs), and monocyte-derived DCs (DCs) (mDCs).
- The cDCs can be split into two functional states: immature and mature. Mature DCs are experts in antigen presentation, whereas immature DCs are experts in antigen uptake and processing.
- Observations indicate that juvenile cDCs can generate immunological tolerance, whereas mature cDCs can induce Th2 or Th1 immune responses.
- It is important to note that distinct subpopulations of DCs might release distinct cytokine patterns, leading in the development of distinct immune responses.
- In addition, DCs are involved in the pathophysiology of a number of disorders, including contact hypersensitivity, autoimmune diseases, and cancer, but they can also be utilised as therapeutic agents in these conditions.
- Dendritic cells (DCs) are antigen-presenting cells with a unique shape and expression of CD11c and major histocompatibility complex class II molecules, among others (MHCII).
- In addition, DCs can identify infections, indications of tissue injury, and tumour antigens before migrating to secondary lymphoid organs, where they present antigens and activate T cells. DCs can stimulate the development of several immune responses, including Th1, Th2, Treg, and Th17.
- There is a wide range of DCs with distinct phenotypes and localizations that create a cellular system that is responsible for immune monitoring and is spread throughout the body.
- DCs are categorised as conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (DCs) (mDCs).
- There are numerous forms of DCs with distinct characteristics and locations. DCs are typically classified as conventional, plasmacytoid, or monocyte-derived.
- cDCs can be categorised as cDC1s and cDC2s. CD8+ CD103+ in mice and BDCA3+ (CD141+) in humans are defining characteristics of cDC1s.
- In mice, the phenotype of CDC2 is CD11b+ CD4+ CD8, but in humans it is BDCA1+ (CD1c+).
- In mice, plasmacytoid pDCs express B220, mPDCA1, and Siglec-h, whereas in humans, they express BDCA4 and BDCA2.
- mDCs are a subset of DCs produced from monocytes that only arise in response to inflammation.
- Langerhans cells, which are normal residents of the epidermis and epithelia, are not regarded to be of the same lineage as the DCs described above since they derive from precursor cells that moved to the skin before birth and developed into LCs during the first week of life.
- In terms of their origin, DCs are distinct from bone marrow progenitor cells, which express Flt3 and occasionally M-CSFR.
- DCs are abundant in lymphoid tissues and epithelia. Additionally, DCs can express different molecular markers based on their location.
- Consequently, pDCs, CD1s, and CD2s can be found in various tissues of the body. It is essential to consider the phenotype and location of DCs in relation to their function on a given tissue.
- DCs are sentinel cells responsible for the identification of pathogens and indications of tissue damage, which promotes their migration to lymphoid organs to activate various subsets of T, natural killer (NK), NKT, and B lymphocytes.
- Long-term research has also revealed that the inflammatory or tolerogenic milieu created by the cytokines present in tissues is crucial for determining the functions that DCs can perform.
- In addition to the cytokines involved in their activation, it is crucial to understand the diverse types of DCs found in lymphoid organs, skin, the gastrointestinal tract, and the blood.
DCs in lymphoid organs
- One of the subsets of DCs found in lymph nodes is CD103+ migrating cDCs from peripheral tissues, which exhibit a mature phenotype characterised by an increase in MHCII, CD80, CD86, and CD40.
- There are also two types of resident DCs: CD8+, CD4+, or CD11b+ cells with an immature phenotype, unless the lymph node contains an inflammatory environment.
- All DCs in the spleen are CD8+ and comprise around 20% of all spleen cells. DCs are categorised into subgroups based on CD11b expression.
- At least three groups of DCs are present in the thymus: CD8+ cDCs (50%) Sirp+ cDCs (20%) and pDCs (30%).
- Several cell lines, including granulocytes, monocytes, and lymphocytes, can be identified in the blood, and in order to examine blood DCs, several lineage markers (Lin), such as CD3, CD19, CD14, CD20, and CD56, are employed to segregate populations of DCs using flow cytometry assays. Thus, cDC and pDC populations may be recognised in blood because they are Lin.
- In the epidermis and dermis, various types of DCs are present. LCs comprise 2% to 4% of the epidermis and express high amounts of Langerin (CD207), CD45, and low concentrations of CD11c and MHCII.
- Intestinal DCs are found in the lamina propria of the intestinal mucosa, particularly in Peyer’s patches.
- These cells are often CD103+, CD8+, and CD207+, express modest levels of MHCII, and have been seen to proliferate when Flt3 levels are high.
- A second group of DCs also resides in the lamina propria, but expresses the markers CD103 and CD11b to a lesser extent than CD103.
- These DCs can also be seen in the muscle layer of the gastrointestinal tract, therefore they may be mistaken for CD11b+ macrophages.
Structure of Dendritic cells
- Dendritic cells are bigger antigen-presenting cells with comparable dendrite-like cytoplasmic extensions to nerve cell dendrites.
- The morphology of the cells is uneven, and they include phase-dense granules, an irregular nucleus, and a tiny nucleolus.
- The cell’s protrusions stretch in multiple directions from the cell body and are responsible for patrolling for invading infections.
- The development of unique dendrites by dendritic cells is essential for the morphological identification of DC in a blood sample.
- There are no filaments in the cytoplasm of dendritic cells, however organelles such as mitochondria and Golgi complex can be detected.
- In a similar manner, dendritic cells at various stages of maturity contain distinct types of granules. The size and distribution of granules in dendritic cells vary, although melanin granules are the most common granules seen in dendritic cells.
Dendritic cell maturation
- Derived from progenitor cells in the bone marrow, immature DCs travel to virtually all lymphoid and nonlymphoid tissues in the body, such as the skin, lungs, and intestines.
- On the road from common DC progenitors to mature DCs, numerous transcription factors, signalling molecules, growth factors, cytokines, chemokines, and adhesion receptors have been implicated.
- In addition, immature DCs receive and process additional maturation signals by identifying damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) in their local environments via a variety of surface pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs).
- This detection of damaged cells or infections enables DCs to protect the integrity of the body through their sentinel-like capabilities.
- In response to chemotactic signals, maturing tissue DCs modify their surface chemokine receptor and adhesion molecule profiles in accordance with microenvironmental cues and migrate to secondary lymphoid organs.
- Immature resident or entering nonresident DCs can be further activated and differentiated into mature, functional DCs within lymphoid tissues.
- Mature DCs are able to process and deliver antigens in the context of self-MHC antigens to CD4+ or CD8+ T cells that are not yet activated. This results in either the activation of primary immunological responses against foreign antigens or the downregulation of T cell reactivity against self antigens.
- Mature DCs stimulate naive T cells via their enhanced surface expression of peptide-loaded major histocompatibility complex (MHC) antigens, costimulatory (or coinhibitory) receptors and ligands, such as CD80 and CD86, and the production of cytokines such IL-6, IL-12p70 or interferons (IFNs).
- T cells can fine-tune the characteristics of mature DCs. Responding T cells may regulate DCs through CD40-CD40L interactions or T cell-derived cytokines such as IL-4 or IFN-γ, for example.
- Thus, T cells may additionally train professional APCs, which can induce various types of immunity or tolerance reliant on T cells.
Mechanism of Dendritic Cells in Immunity
- Dendritic cells serve an important role in the immune system. In our innate and adaptive immune processes, they function as phagocytes, antigen-presenting cells, and accessory cells (messengers and activators).
- One of three types of antigen-presenting cells, dendritic cells develop from precursor cells in bone marrow and lymph tissue.
- Antigen-presenting cells allow T lymphocytes to identify and eliminate antigens, which are foreign or dangerous substances.
- Without antigen-presenting cells, T lymphocytes would not respond to potentially harmful particles that enter the body or are created within it. Antigen-presenting cells (APCs) are composed of dendritic cells, macrophages, and B-cells.
- Dendritic cells are dispersed throughout the body and cluster in places that contribute to rapid immunological responses, including the lungs, gut, blood, and lymphoid tissues. These tissues must endure constant antigen assaults.
- Dendritic cells first arise in various tissues and organs as immature cells. Only after antigen capture do they mature; only after antigen capture are they referred to as antigen-presenting cells (APCs).
- As antigen-presenting cells, mature dendritic cells move to lymph nodes and present their acquired antigens to T lymphocytes.
- Dendritic cells play a crucial role in the innate immune system, where they perform antigen monitoring in the form of endogenous poisons and exogenous foreign chemicals.
- Antigens, or the surface proteins of antigens, stimulate an immune response. This is because certain molecular patterns on antigens or damaged cell membranes make them identifiable.
Dendritic Cell Function in Innate Immune System
- Before, at, or shortly after antigen exposure, the innate immune system provides a nonspecific mechanism of defence.
- Antigens include viruses and bacteria as well as substances generated by injured cells when they are burned, scraped, oxygen-deprived, or otherwise traumatised.
- The majority of vertebrates have several defences. These include the skin, stomach acid, mucus in the airways, the blood-brain barrier, perspiration, and tears. The innate immune system includes these structural barriers.
- If an antigen penetrates the body and survives these anatomical barriers, the subsequent phase of the innate immune system’s defence mechanism is activated.
- PAMPs (pathogen-associated molecular patterns) are common patterns of molecules found on the outer surfaces of all microorganisms.
- When our own cells are injured, dying, or dead, they contain DAMPs (damage-associated molecular patterns).
- The figure below depicts the invasion of pink antigen bacteria with LPS (lipopolysaccharide) PAMPs on their outer membranes.
- PAMPS are detected by LPS receptors on the surface of macrophages. In reaction to detection, the macrophage secretes cytokines. Cytokines alert other cells that an assault is imminent. Bacteria are captured and digested by the macrophage (phagocytosis).
- Numerous cell types, including dendritic cells, contain receptors for pattern recognition (PRRs). A single pattern recognition receptor can distinguish patterns associated with both pathogens and damage.
- The initial phase following PAMP or DAMP identification is the inflammatory response. By increasing blood flow to the region, more white blood cells are dispatched to eliminate the intruders.
- Many bacteria die at temperatures above the normal body temperature, therefore a fever is beneficial. Every day, coughing and sneezing rid us of innumerable diseases.
- Chemical agents such as histamine, prostaglandin, and bradykinin are released by white blood cells. These substances dilate nearby blood arteries and attract additional phagocytic cells.
- Phagocytic cells engulf and digest foreign particles and poisons. Like macrophages and neutrophils, dendritic cells are phagocytes.
- Macrophages and neutrophils scavenge and eliminate toxic or foreign particles and emit substances that attract other white blood cells.
- Dendritic cells engage in phagocytosis and store information from ingested particles, which can initiate adaptive (acquired) immune responses.
- Cytokines are molecules that send signals. This category contains interferons, which you may recognise as the active ingredient in certain antiviral medications.
- Cytokines induce or inhibit cellular proliferation, apoptosis, inflammation, differentiation, and migration.
- As autocrine messengers, they influence their own cell; as paracrine messengers, they influence neighbouring cells; and as bloodstream messengers, they influence distant destinations.
Dendritic Cells Function in Innate Immunity to Adaptive Immunity
- After antigen capture, the most critical function of dendritic cells is the activation of naive T lymphocytes.
- Similar to dendritic cells, T-lymphocytes (T cells) change their state when they encounter and recognise an antigen.
- The original form of a mature T-lymphocyte as it leaves the lymphoid organ of the thymus is characterised as nave.
- After contacting an antigen-presenting dendritic cell (or other APC type), a naive T-lymphocyte develops into an effector T cell.
- As an effector cell, it is capable of destroying the presenting antigen. Effector T cells are frequently referred to as cytotoxic T cells.
- The majority of effector T cells die once an antigen has been eliminated; however, a tiny percentage develops into memory T cells.
- Memory T-cells underpin our acquired (adaptive) immune response. They remember the antigen and will fight it if it re-enters the body.
Dendritic Cells in Cancer Therapy
- The application of dendritic cells in cancer therapy is the subject of extensive scrutiny. To move toward individualised cancer treatment in the form of a vaccine or even a prophylactic pill, we must have a far deeper understanding of how they function.
- Vaccination against cancer is a sort of immunotherapy. Relevant is the ability of dendritic cells to govern our immune responses, as somewhere along the cancer path our immune systems fail to recognise and destroy aberrant cells.
- As dendritic cells – and all antigen-presenting cells – are susceptible to being deceived by cancer cells, loading them with a tumour antigen outside the body before injecting them into the body could produce the desired immune response. No longer would cancer cells be allowed to flourish unchecked.
- Tumor cells inhibit the action of the immune system, including dendritic cell activity. Tumor cells conceal themselves behind their own anti-inflammatory cytokines.
- Not only are they difficult for APCs to identify, but they also inhibit the normal inflammatory response of healthy immune cells. Cancer cells can proliferate unimpeded and undetected.
- Dendritic cells are straightforward to cultivate in the laboratory. This makes them an attractive candidate for use in cancer vaccinations.
- Current research investigates whether preloading dendritic cells with specific cancer antigens in the laboratory and then injecting them into the body could one day serve as a cancer treatment.
- As the mechanism of immunity is not yet fully understood, and as individual physiological parameters react extremely differently to therapy, the findings of clinical trials are inconsistent.
Types of Dendritic Cell
There are three major dendritic cell types in humans. These are typical dendritic cells, plasmacytoid dendritic cells, and epidermal (dermal) dendritic cells.
1. Plasmacytoid Dendritic Cells
- Plasmacytoid dendritic cells are derived from lymphoid organs (lymph nodes, thymus, spleen, and tonsils) and bone marrow. Lymph vessels and nodes (green) travel along the same pathways as our blood vessels (blue and red).
- Plasmacytoid dendritic cells generate cytokines such as interferon type I and tumour necrosis factor. The generation of natural killer cells, B lymphocytes, and myeloid dendritic cells is stimulated by cytokines. They also possess exceptional antiviral effects.
2. Conventional Dendritic Cells
- Once in the bloodstream, conventional dendritic cells, also known as classical or myeloid dendritic cells, develop into three distinct cell types.
- These forms reach the lungs, digestive tract, liver, and kidneys.
3. Epidermal Dendritic Cells
- There are various types of epidermal and dermal dendritic cells on and within the skin. All epidermal dendritic cells stimulate epidermal and dermal T-cells.
- An illustration is the Langerhans cell (LC). Langerhans cells travel from the epidermis to the lymph nodes, carrying an antigen to present to a naive T cell.
- They accomplish this by promoting the differentiation of T cells into T helper cells. This differentiation takes place in glands near to the antigen location. T helper cells assist B cells in producing antibodies, as their name implies.
- Other types of epidermal dendritic cells are generated in the bone marrow and undergo differentiation in the blood and skin.
- The majority of our understanding of these cells is derived from rodent models, typically mice. We do not fully understand how these cells function in the human body.
- During inflammation, monocyte-derived dendritic cells create a new subpopulation of dendritic cells.
- Monocytes that develop into dendritic cells are CCR2-positive monocytes that move to the site of inflammation from the bone marrow.
- During bacterial infections, these monocyte-DCs provide protection to the cells of the innate immune system.
5. Migratory DCs
- Monocyte-derived dendritic cells generate a new subset of dendritic cells during inflammation.
- Monocytes that transform into dendritic cells are CCR2-positive monocytes that migrate from the bone marrow to the site of inflammation.
- During bacterial infections, these monocyte-DCs safeguard the innate immune cells.
Functions of Dendritic cells
The following are some of dendritic cells’ functions:
- Dendritic cells are professional antigen-presenting cells whose most significant role is to present antigens to various immune cell receptors for their activation.
- Dendritic cells induce an immunological response in T-cells and participate in the development of T-helper cells.
- Dendritic cells are involved in the activation of natural killer cells via the production of several cytokines in the innate immune system.
- Dendritic cells have also been implicated in the functional regulation of regulatory T cells.
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