Dendritic Cells- Definition, Structure, Immunity, Types, Functions

The immune system is a complex network of cells and molecules that protect the body from infections and diseases. The immune system can be divided into two main branches: the innate immune system and the adaptive immune system. The innate immune system is the first line of defense that responds quickly and non-specifically to any foreign substance or pathogen. The adaptive immune system is the second line of defense that responds slowly but specifically and memorably to a particular antigen.

An antigen is any substance that can trigger an immune response. Antigens can be derived from bacteria, viruses, fungi, parasites, toxins, or even self-cells. However, not all antigens can directly activate the adaptive immune system. Most antigens need to be processed and presented by specialized cells called antigen-presenting cells (APCs). APCs are cells that can capture, process, and display antigens on their surface in association with molecules called major histocompatibility complex (MHC). MHC molecules are proteins that bind to antigens and present them to T cells, which are a type of white blood cell that can recognize and respond to specific antigens.

There are different types of APCs in the immune system, such as macrophages, B cells, and dendritic cells. Among them, dendritic cells are considered to be the most potent and efficient APCs. Dendritic cells are named after their distinctive shape, which resembles the branching projections of nerve cells called dendrites. Dendritic cells are widely distributed in various tissues of the body, especially those that are exposed to the external environment, such as the skin, mucous membranes, lungs, and intestines. Dendritic cells act as sentinels that constantly patrol for invading pathogens and capture them by various receptors on their surface. Once they encounter an antigen, they undergo a process of maturation and migration to the lymph nodes, where they present the antigen to T cells and initiate an adaptive immune response.

Dendritic cells play a crucial role in bridging the innate and adaptive immune systems. They not only present antigens to T cells but also provide additional signals that determine the type and magnitude of the immune response. Dendritic cells can also activate other types of immune cells, such as B cells and natural killer (NK) cells. Furthermore, dendritic cells can modulate the balance between immunity and tolerance by regulating the function of regulatory T cells, which are a subset of T cells that can suppress excessive or harmful immune responses.

Dendritic cells are a heterogeneous group of cells that consist of multiple subsets with different origins, phenotypes, functions, and locations. The classification and nomenclature of dendritic cell subsets are still evolving and vary among different species. However, some common subsets of dendritic cells include plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), migratory dendritic cells (mDCs), and monocyte-derived dendritic cells (moDCs). Each subset of dendritic cells has distinct roles in immunity and inflammation.

In this article, we will discuss the structure, immunity, types, and functions of dendritic cells in detail. We will also explore how dendritic cells interact with other immune cells and how they contribute to various diseases and disorders.

Dendritic cells are larger antigen-presenting cells with large cytoplasmic projections that are similar in structure to dendrites of nerve cells. The cells are irregular in shape with phase-dense granules, an irregular nucleus, and a small nucleolus. The projections from the cell extend in many directions from the cell body, which are involved in patrolling for invading pathogens.

The distinctive dendrite formation by dendritic cells is an important feature for the morphological identification of DC in a blood sample. The cytoplasm of dendritic cells does not have any filaments, but cell organelles like mitochondria and Golgi complex can be observed. Similarly, dendritic cells at different stages of maturation have different types of granules. The size and occurrence of granules in dendritic cells are diverse, but the most common granules occurring in dendritic cells are melanin granules.

The cell surface of dendritic cells is covered with various receptors that recognize and bind to antigens, cytokines, and pathogen-associated molecular patterns (PAMPs). Some of the receptors expressed by dendritic cells are:

• Toll-like receptors (TLRs): These are pattern recognition receptors that recognize conserved molecular structures on microbes and activate signaling pathways that induce inflammatory responses and maturation of dendritic cells.
• C-type lectin receptors (CLRs): These are carbohydrate-binding receptors that recognize glycan structures on pathogens and mediate endocytosis and antigen presentation.
• Fc receptors: These are receptors that bind to the Fc portion of antibodies and mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.
• Scavenger receptors: These are receptors that bind to modified lipoproteins and apoptotic cells and mediate clearance of cellular debris and cholesterol homeostasis.
• Chemokine receptors: These are receptors that bind to chemokines and mediate chemotaxis and migration of dendritic cells.

The expression of these receptors varies depending on the type, location, and maturation state of dendritic cells. The receptor expression also influences the function and interaction of dendritic cells with other immune cells.

Dendritic cells occur in almost all types of tissue in the human body, where they act as a link between the innate and adaptive immune systems. The dendritic cells in these tissues can exist as either mature cells or immature cells. The immature dendritic cells undergo maturation in the presence of either antigens or cytokines or pathogen-associated molecular patterns (PAMPs). Maturation of such cells activates the metabolic, cellular, and gene transcription of the cells, causing the cells to migrate from peripheral tissues to T-dependent areas in lymphoid organs.

The process of maturation causes the loss of adhesive structures, reorganization of the cytoskeleton, and increase in motility. It also leads to a decrease in their endocytic activity and an increased expression of MHC-II and costimulatory molecules.

Adaptive immune response

The mature dendritic cells express a high level of the chemokine receptor CCR7 and cytokines, both of which are important for T-cell activation.The interaction between the dendritic cells and T cells forms the basis of antigen-specific immune responses. The interaction also induces the differentiation of T cells into different T helper subsets.Dendritic cells also have a unique characteristic of cross-presentation as these can trigger responses against intracellular antigens from different cell types.The activation of a T cell response by dendritic cells has been attributed to a combination of factors like a high level of expression of cell membrane costimulatory proteins.Dendritic cells also play an important role in directing an appropriate type of immune response against the invading microorganisms. These cells express different polarizing signals depending on the type of receptors linked with the cell surface.Dendritic cells also regulate B-cell responses as DCs can form T-independent short-lived clusters with B cells for their activation.

Innate immune response

Even though the activation of adaptive immune response is the primary mechanism of dendritic cells, studies have revealed that these cells are important during the early phases of the immune response in innate immunity.Dendritic cells activate NK cells in lymph nodes by the secretion of cytokines like IL-2 and INF-γ that are essential for NK cell proliferation.The mechanism of DC-mediated NK cell activation is an important pathway for the activation of cells of innate immunity.Dendritic cells activated in the presence of microorganisms can also induce NK-cell cytotoxic function.

The adaptive immune response is a specific and long-lasting response that involves the activation and differentiation of T cells and B cells. T cells are lymphocytes that can recognize antigens presented by MHC molecules on the surface of antigen-presenting cells (APCs) such as dendritic cells. B cells are lymphocytes that can produce antibodies against specific antigens.

Dendritic cells play a crucial role in initiating and regulating the adaptive immune response by presenting antigens to T cells and B cells. Dendritic cells can capture antigens from different sources, such as pathogens, dying cells, or vaccines, and process them into peptides that bind to MHC molecules. The MHC-peptide complexes are then displayed on the surface of dendritic cells, along with costimulatory molecules and cytokines, that provide signals for T cell activation.

Dendritic cells can migrate from the site of antigen capture to the secondary lymphoid organs, such as lymph nodes or spleen, where they encounter naive T cells. The interaction between dendritic cells and T cells is facilitated by chemokines and adhesion molecules that guide the cell migration and contact. The antigen presentation by dendritic cells triggers the activation, proliferation, and differentiation of T cells into different subsets, such as helper T cells (Th), cytotoxic T cells (Tc), or regulatory T cells (Treg).

Helper T cells are T cells that secrete cytokines that help other immune cells to perform their functions. Depending on the type of cytokines produced, helper T cells can be further classified into Th1, Th2, Th17, or Tfh subsets. Th1 cells produce interferon-gamma (IFN-γ) and interleukin-2 (IL-2) that promote cell-mediated immunity against intracellular pathogens. Th2 cells produce interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) that promote humoral immunity against extracellular pathogens. Th17 cells produce interleukin-17 (IL-17) and interleukin-22 (IL-22) that promote inflammation and mucosal immunity against fungal and bacterial infections. Tfh cells produce interleukin-21 (IL-21) and express CXCR5 that help them to migrate to the follicles of lymphoid organs and provide help to B cells.

Cytotoxic T cells are T cells that can kill infected or abnormal cells by releasing perforin and granzymes that induce apoptosis. Cytotoxic T cells recognize antigens presented by MHC class I molecules on the surface of target cells. Cytotoxic T cells can also secrete cytokines such as IFN-γ and tumor necrosis factor-alpha (TNF-α) that enhance the killing activity.

Regulatory T cells are T cells that can suppress the immune response and maintain self-tolerance by inhibiting the activation and function of other immune cells. Regulatory T cells express high levels of CD25 and Foxp3 transcription factor. Regulatory T cells can also secrete anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β).

Dendritic cells also play an important role in activating B cells by presenting antigens to them or by providing help from helper T cells. Dendritic cells can capture antigens from the blood or lymph and transport them to the follicles of lymphoid organs where they encounter naive B cells. The antigen presentation by dendritic cells stimulates the activation, proliferation, and differentiation of B cells into plasma cells or memory B cells.

Plasma cells are B cells that secrete large amounts of antibodies against specific antigens. Antibodies are proteins that can bind to antigens and neutralize them or mark them for destruction by other immune mechanisms. Antibodies can also activate the complement system that enhances the immune response.

Memory B cells are B cells that persist in the body after an infection or vaccination and provide a rapid and enhanced response upon re-exposure to the same antigen. Memory B cells express high levels of MHC class II molecules and costimulatory molecules that allow them to interact with helper T cells more efficiently.

In summary, dendritic cells are essential for initiating and regulating the adaptive immune response by presenting antigens to T cells and B cells and providing signals for their activation, proliferation, differentiation, and memory formation.

The innate immune response is the first line of defense against pathogens that involves nonspecific recognition and elimination of foreign invaders. The innate immune system consists of various cells and molecules that can rapidly respond to pathogens without prior exposure or memory. Some of the cells involved in the innate immune response are natural killer (NK) cells, macrophages, neutrophils, mast cells, eosinophils, basophils, and dendritic cells (DCs).

NK cells are a type of lymphocyte that can kill infected or abnormal cells by releasing cytotoxic granules containing perforin and granzymes. NK cells can also secrete cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) that can modulate the immune response and activate other immune cells. NK cells can recognize target cells by using various receptors that can either activate or inhibit their function. Some of the activating receptors are natural cytotoxicity receptors (NCRs), NKG2D, CD16, and DNAM-1. Some of the inhibitory receptors are killer cell immunoglobulin-like receptors (KIRs), NKG2A, and CD94.

Dendritic cells play a crucial role in activating NK cells in the innate immune response. DCs can sense pathogens by using pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), and retinoic acid-inducible gene-I-like receptors (RLRs). Upon recognition of pathogen-associated molecular patterns (PAMPs), DCs undergo maturation and migration to the lymph nodes where they encounter NK cells. DCs can activate NK cells by several mechanisms:

• DCs can directly present antigens to NK cells via MHC class I molecules or NKG2D ligands. This can trigger the activation of NK cells that express CD16 or NKG2D receptors, respectively.
• DCs can indirectly present antigens to NK cells by transferring them to other antigen-presenting cells (APCs) such as macrophages or B cells. This can activate NK cells that express NCRs or DNAM-1 receptors, respectively.
• DCs can secrete cytokines such as IL-12, IL-15, IL-18, and type I interferons that can stimulate the proliferation, differentiation, and activation of NK cells.
• DCs can form immunological synapses with NK cells that allow the exchange of membrane-bound molecules and signals. This can enhance the adhesion, polarization, and cytotoxicity of NK cells.

The activation of NK cells by DCs can have several outcomes:

• NK cells can kill infected or abnormal target cells by releasing cytotoxic granules or expressing death ligands such as FasL or TRAIL.
• NK cells can produce cytokines such as IFN-γ and TNF-α that can enhance the adaptive immune response by activating T cells and B cells.
• NK cells can regulate the function of DCs by killing immature DCs or promoting the maturation of mature DCs.

Therefore, dendritic cells are important mediators of the innate immune response by activating NK cells that can eliminate pathogens and modulate the adaptive immune response.

Dendritic cells are a heterogeneous group of cells that can be classified into different types based on their origin, location, phenotype, and function. The following are some of the major types of dendritic cells and their functions:

• Plasmacytoid dendritic cells (pDCs): These are dendritic cells that resemble plasma cells and express markers such as B220 and PDCA1. They are mainly found in the blood, lymphoid organs, and mucosal tissues. They are specialized in producing large amounts of type I interferons (IFNs) in response to viral infections. They can also present antigens to T cells and B cells and induce tolerance or immunity depending on the context.

• Conventional dendritic cells (cDCs): These are dendritic cells that express markers such as CD11c and MHC-II. They are derived from hematopoietic stem cells in the bone marrow and can be further divided into two subsets: CD8α+ cDCs and CD11b+ cDCs. CD8α+ cDCs are mainly found in the spleen, thymus, and lymph nodes. They are efficient at cross-presenting antigens to CD8+ T cells and inducing cytotoxic T cell responses. CD11b+ cDCs are mainly found in non-lymphoid tissues such as the skin, lung, and intestine. They are efficient at presenting antigens to CD4+ T cells and inducing helper T cell responses.

• Migratory dendritic cells (mDCs): These are dendritic cells that migrate from peripheral tissues to lymphoid organs after encountering antigens or inflammatory stimuli. They can be further divided into two subsets: CD103+ mDCs and CD103- mDCs. CD103+ mDCs are mainly found in epithelial tissues such as the skin, gut, and lung. They express integrin αEβ7 (CD103) and CCR7. They can present antigens to T cells in the draining lymph nodes and induce mucosal immunity. CD103- mDCs are mainly found in non-epithelial tissues such as the liver, aorta, and brain. They express CCR7 but not CD103. They can also present antigens to T cells in the draining lymph nodes and induce systemic immunity.

• Monocyte-derived dendritic cells (moDCs): These are dendritic cells that differentiate from monocytes in response to inflammation or infection. They express markers such as CD11b, CD14, and CCR2. They can migrate from the blood to the site of inflammation or infection and phagocytose pathogens or debris. They can also present antigens to T cells and B cells and secrete pro-inflammatory cytokines such as IL-12 and TNF-α.

Dendritic cells perform various functions in the immune system depending on their type and activation state. Some of the common functions of dendritic cells are:

• Antigen presentation: Dendritic cells can capture, process, and present antigens to different types of immune cells such as T cells, B cells, NK cells, NKT cells, and γδ T cells. They can also cross-present antigens from other cell types or extracellular sources to activate cytotoxic T cell responses.

• Immune activation: Dendritic cells can activate immune responses by providing costimulatory signals and cytokines to immune cells. They can also polarize immune responses by inducing different subsets of helper T cells such as Th1, Th2, Th17, or Treg.

• Immune regulation: Dendritic cells can regulate immune responses by inducing tolerance or anergy in immune cells. They can also modulate immune responses by producing anti-inflammatory cytokines such as IL-10 or TGF-β.

Dendritic cells are essential for the initiation and regulation of both innate and adaptive immune responses. They play a key role in defending against pathogens, maintaining homeostasis, and preventing autoimmunity.

Dendritic cells are not only involved in the activation of adaptive and innate immune responses, but also play a role in the regulation of inflammation. Inflammation is a protective response of the body to tissue damage or infection, which involves the recruitment of immune cells and the release of inflammatory mediators. However, excessive or chronic inflammation can lead to tissue damage and disease.

Dendritic cells can modulate inflammation by producing anti-inflammatory cytokines, such as IL-10 and TGF-β, which can inhibit the activation of pro-inflammatory cells, such as macrophages and T cells. Dendritic cells can also induce the differentiation of regulatory T cells (Tregs), which are a subset of T cells that suppress the immune response and maintain immune tolerance. Tregs can prevent autoimmune diseases, allergic reactions, and transplant rejection.

Dendritic cells can also sense the level of inflammation and adjust their maturation and migration accordingly. For example, in the presence of high levels of inflammatory cytokines, such as TNF-α and IL-6, dendritic cells can mature rapidly and migrate to the lymph nodes to activate T cells. However, in the presence of low levels of inflammatory cytokines, dendritic cells can remain immature and reside in the peripheral tissues to maintain immune tolerance.

Dendritic cells originate from hematopoietic stem cells (HSCs) in the bone marrow, which are the source of all blood cells. HSCs can differentiate into two types of progenitor cells: common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CMPs can give rise to monocytes, macrophages, granulocytes, megakaryocytes, and erythrocytes. CLPs can give rise to B cells, T cells, NK cells, and plasmacytoid dendritic cells (pDCs).

Conventional dendritic cells (cDCs) and monocyte-derived dendritic cells (moDCs) are derived from CMPs. cDCs develop from a specific subset of CMPs called common dendritic cell progenitors (CDPs), which express the transcription factor Zbtb46. CDPs can further differentiate into pre-cDCs, which migrate from the bone marrow to the blood and then to various tissues. In the tissues, pre-cDCs can differentiate into different subsets of cDCs depending on the local microenvironment.

moDCs develop from monocytes that are released from the bone marrow to the blood. Monocytes can differentiate into moDCs under inflammatory conditions or in response to certain stimuli, such as GM-CSF or IL-4. moDCs can migrate from the blood to the inflamed tissues or lymph nodes.

pDCs develop from CLPs that express the transcription factor E2-2. CLPs can differentiate into pre-pDCs, which migrate from the bone marrow to the blood and then to various lymphoid organs. In the lymphoid organs, pre-pDCs can differentiate into pDCs.

Dendritic cells are constantly replenished from the bone marrow progenitors throughout life. However, their lifespan and turnover rate vary depending on their type and location. For example, cDCs in the spleen have a half-life of about 7 days, while moDCs in the skin have a half-life of about 2 days.

Dendritic cells are essential components of the immune system that perform various functions in both innate and adaptive immunity. They are the key antigen-presenting cells that can activate and regulate different types of immune cells, such as T cells, B cells, and NK cells. They can also modulate the type and intensity of the immune response by producing different cytokines and costimulatory molecules. Dendritic cells are heterogeneous and consist of several subsets that have distinct phenotypes and functions. Dendritic cells originate from bone marrow and migrate to different tissues where they encounter pathogens and undergo maturation. They then travel to lymphoid organs where they present antigens to naive T cells and initiate the adaptive immune response. Dendritic cells are also involved in inflammation and tissue homeostasis by interacting with other cells and molecules. Dendritic cells are therefore crucial for the maintenance of immunological balance and protection against infections.

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