**1. Introduction**

DCs represent an important link between innate and adaptive immunity. DCs are heterogeneous population of antigen-presenting cells that are crucial to initiate and polarize the immune response. Although, all DCs are capable of capturing, processing, and presenting antigens to T cells, DCs subtypes differ in origin, location, migration patterns, and specialized immunological roles [1]. All the DCs are continuously renewed by hematopoietic stem cell progenitor cell located in bone marrow, except of Langerhans cells (LCs) that develop from embryonic macrophages in the yolk sac and fetal liver, that are recruited in the epidermis during embryonic life. The process is not clearly, but hematopoietic stem cell is differentiated into granulocyte-macrophage progenitors (GMP) and multilymphoid progenitors (MLP), that have the potential to differentiate into macrophage-dendritic precursor (MPD) or common dendritic cell progenitor (CDP) like progenitor. These progenitors are subsequently differentiated into common monocyte progenitor (cMoPs), plasmacytoid dendritic cells (pDCs) and human equivalent of pre-DC, those are the most important to differentiate all subsets of DCs. cMoPs develop into blood monocytes, which differentiate into monocyte-derived DCs (MoDCs) in inflamed tissues, and

#### **Figure 1.**

*Dendritic cell lineage development. The hematopoietic stem cell located in bone morrow is the progenitor of all DCs. Here the differentiation in multi-lymphoid progenitor and granulocyte-macrophage can become the human equivalent of macrophage-dendritic precursor (MPD) or dendritic cell progenitor (CDP). From this cell arise three important progenitor cells (cMoPs), pDCs and pre-DC, these last cells migrate to bloodstream or target tissue/organ to maturate and differentiate to become one of the different subsets of DCs. Explanation in the text. Figure modified by the authors from reference [3] and authorized to be published by bio-Techne (figure created by Muñoz-Carrillo* et al*., with BioRender.com).*

fully mature pDCs along with unmatured pre-DCs migrate through the blood tissue. Immature human pre-DCs differentiate either in the bloodstream or in tissues following migration, developing thus in different DCs subsets (**Figure 1**) [2–4].

### **2. Dendritic cell subsets**

The DCs are present in lymph organs and non-lymphoid organs, also in blood stream, afferent lymph, and mucous membranes. There are different ways to classify DCs, by its linage, as mentioned above there are cMoPs and pDCs. The cMocPs express typical myeloid antigens as CD11c, but lack of CD14 or CD16 and may be split in CD1c + and CD141+ fractions. While pDCs have expression of CD123, CD303 and CD304, with high or low expression of CD123, CD303 or CD304; the cluster of differentiation is determined in the differentiation of their precursor. These cells cMoPs and pDCs are classified into blood DCs [5, 6].

Inflammatory DCs derived from classical CD14+ blood monocytes, using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4. Monocytes are highly plastic, and they differentiate into DCs or different forms of macrophages (M1/M2). Human inflammatory exudates contain distinct inflammatory DC-like and macrophage-like cells and transcriptional profiling suggests a common monocyte origin. Key features of these cells are the expression of CD1c, CD1a, CD206, FcεR1, Sirpα but lack of CD16 and CD209. Non-classical monocytes and antigen 6-Sulpho LacNac DCs are a heterogeneous population and CD16+ monocytes possess distinct characteristics including higher major histocompatibility complex (MHC) class II and co-stimulatory antigen expression, classify as a type of blood DCs [5].

*Role of Dendritic Cells in Pathogen Infections: A Current Perspective DOI: http://dx.doi.org/10.5772/intechopen.95551*

The functional-anatomical classification of DCs is widely vast, the classification of DCs are dependent of anatomical location or function, for example, DCs in heart are known as interstitial cells, in ganglia are known as interdigitating cells, but when DCs are in the afferent lymph are called veiled cells. Also, the function of these are different but sequential [5, 6]. Intestinal DCs are found in small intestine, lamina propia and gut associated lymphoid tissue. This DCs express CD103 and Sirpα in three different ways, such as CD103 + Sirpα- DCs, The CD103 + Sirpα+ DCs and CD103- Sirpα+ DCs. Most of these cells are located deeper into lamina propia, and express CD45, human leukocyte antigen-DR isotype (HLA-DR), CD14, CD64 and high levels of CX3C chemokine receptor 1(CX3CR1), and since these cells do not migrate to the lymph nodes, they have been depicted as intestinal macrophages. In the mesenteric lymph node DCs are a mixture of cells found in the peripheral blood. Such as peripheral blood, where soluble food bioactives may also be directly available for internalization by DCs in the draining lymph nodes *via* the conduit system [7].

LCs and microglia are two specialized self-renewing DCs, found them in stratified squamous epithelium and parenchyma of the brain, respectively. The LCs differentiate into migratory DCs, whereas microglia are considered as a type of specialized macrophage. There are DCs found in tissues and lymph nodes with marker CD14+, a subset of CD11c+, found in interstitial DCs; but they are more monocyte-like or macrophage-like, that may arise from classical monocytes [5].

#### **2.1 Morphology**

Immatures and matures DCs have different morphologic, immatures DCs monocyte-derived are spherical, irregular shape, with little cytoplasmatic projections, also abundant phase-dense granules (birbeck's granules or bodies) and irregular nucleus with small nucleoli. Once the DCs maturates shows stellate process, giving veiled appearance, with more extended dendrites projecting in many directions from the body cell [6, 8].

#### **2.2 Maturation**

The DCs have 3 stages precursor, immature and mature stage, but some authors do not count the precursor phase [6, 9]. Precursor phase course with any of the principal precursor as cMoPs, pDCs or Human equivalent of pre-DCs. It migrates from bone morrow to specific tissue or area, process leaded by chemokine chemoreceptors such as C-C chemokine receptor type 1 (CCR1), CCR5 and CCR6 and by adhesion molecules CD26P ligand. When the cell arrives to the corresponding tissue or place, it becomes immature DC. The immature DC express CCR1 and CCR3, where its ligand is in endothelium and inflammatory cells, promoting its migration to different organs and inflammatory tissues. This immature DC is capable of capture antigens by different receptors like Fc receptor, integrins, type C lectin and scavenger receptors such as lectin-type oxidized LDL receptor 1 (LOX-1) and CD91. Immature DC is characterized for various amounts of chemokines, so it can be extravasated to inflammatory tissue [6].

Once the DC has captured the antigen, this one is degraded to peptides that will get bind to MHC class I or class II. The endogenous antigens are processed by MHC class I, while exogenous antigens are processed by MHC class II. The lipidic antigens are presented by different molecules CD1(a-d) to T cell receptor (TCR) or natural killer T (NKT) cell. The differentiation process of immature DC to mature DC needs different signals to complete the process. To the immature DC gets mature, needs to stimulate T lymphocyte. This is possible when the antigen is presented to T lymphocyte by MHC class I or class II to TCR receptor and interaction of costimulatory molecules (CD28, CD40, CD54, CD58, CD80, CD83 and CD86) to activate T lymphocyte. Other molecules like adhesion (CD58, CD54) danger signal (CD40 ligand, tumor necrosis factor (TNF)-α, IL-1, IL-6, Interferon (INF)-α and Toll-like receptors (TLRs) agonist) [6, 8]. When the DC becomes mature, decreases the chemokine receptor expression of CCR1 and CCR5, whereas CCR7 increases. The CCR7 ligand is in ganglia walls and ganglionic paracortical zone. There, the mature DC secretes chemokines such as thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) or interferon gamma-induced protein 10 (IP-10), which recruits different types of T lymphocytes, monocytes, regulated on activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α and MIP-β, to the local microenvironment [6].

#### **2.3 Functions**

DCs cells have many functions, but these can be globed within three functions. The first one is the main function as antigen presentation and activation of T lymphocytes as inducing adaptative immunity, with important release of cytokines for example IL-12 to differentiate T lymphocytes in T helper cell or cytotoxic lymphocytes. DCs have a wide range of properties including potent stimulation of native CD4+ T cells, cross-presentation to CD8<sup>+</sup> T cells and production of proinflammatory cytokines IL-1, IL-6, TNF-α, IL-12 and IL-23 [5, 9, 10]. The second function to induce tolerance. There are 2 types of tolerance central and peripheral. Central tolerance develops in thymus where a tolerance upon our own antigens occurs, and the reactive T lymphocytes to those antigens are destroyed, this also happen in bone morrow for B lymphocytes. The peripheral tolerance occurs when costimulatory molecules, last step of antigen presentation is not complete, there is a failure in activation of T lymphocyte, so the T lymphocyte become tolerogenic [6, 9, 10]. The third function to maintain immune memory in tandem with B cells. As mentioned before, there are population of DCs in ganglia, in the germinal center are found the follicular DCs which seems to be a reservoir of antigen and antibody complexes, that last an exceptionally long time up to months or years. This allows a constant stimulation of B cells to maintain memory [9].

There are others important functions of DCs, as their role in innate immunity, the DCs have pattern recognition receptor (PRR) and pathogen-associated molecular pattern (PAMPs) [10]. These receptor patterns activate TLR pathways, type C lectins and release pro-inflammatory cytokines to activate innate immunity system [8]. Also, DCs have been related to B lymphocytes proliferation and induction of T lymphocytes to suppress the immune response by missing of costimulatory molecules without IL-12, inducing T lymphocytes to secrete IL-10 and transforming growth factor (TGF)-β [6, 9].

### **3. Role of dendritic cells in viral infection**

Since the discovery of DCs [11], the knowledge of the innate and adaptive immune response has been increasing significantly. At present, DCs are considered a key cell in immune response activation with multiple functions including the virus recognition, processing of viral antigen and as antigen-presenting cells to cells of specific immune response, serving as a bridge between innate and adaptive response [12]. DCs are bone marrow-derived cells and they can be found in different parts of the organism including mucous membrane, the skin, and

#### *Role of Dendritic Cells in Pathogen Infections: A Current Perspective DOI: http://dx.doi.org/10.5772/intechopen.95551*

lymphoid tissue [13]. Depending on surface markers, DCs can be classified as immature or mature myeloid DCs and plasmacytoid DCs [14, 15].

Immature DCs are inactive cell with high capacity to capture viral antigen. They are present in virtually all tissue with high probability to capture invading viruses. Immature DCs lack the capacity of antigen presentation. On the other hand, mature MDC is generated by an immature DC that was activated when recognized and processed viral antigen. Mature DCs function as antigen presenting cells (APCs). They express MHC-II molecules and different co-stimulators surface molecules that give them the antigen presentation capacity. Mature DCs also produce different cytokines to initiate antiviral immune response [16].

Likewise, plasmacytoid DCs also sense viral pathogen. They are called plasmacytoid DCs by its high resemblance to plasma cells. Although pDC has the ability of antigen-presenting, this function is low compared with MDC. However, pDCs contribute to both inflammatory process and antiviral state. They are specialized DCs that produce proinflammatory cytokines and high levels of IFN type I [17]. Both MDC and pDCs are present in lymphatic nodes where they are capable to present viral antigen to naïve T cell [18, 19].
