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Dendritic cells were first described by Paul Langerhans (Langerhans cells) in late nineteenth century. It wasn't until 1973, however, that the term "dendritic cells" was coined by Ralph M. Steinman and Zanvil A. Cohn. Dendritic cells (DCs) are immune cells that form part of the mammalian immune system. DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active by taking up and processing antigens (Ags) after which they undergo further maturation and migrate to secondary lymphoid tissues. Here, they present the Ag on their cell surface linked with Major HistoCompatibility (MHC) molecules to T-cell and induce immune response, thus functioning as Antigen Presenting Cells (APC). DCs now increase scientific and clinical interest due to their key role in anti-cancer host responses, potential use as biological adjuvants in tumour vaccines and their involvement in the immunobiology of tolerance and autoimmunity.
The immune system has multiple ways of recognizing and responding to microbial components and other disease-related stimuli. DC lineage of white blood cells has a great role to control this intricate system. These are antigen presenting cells which process the antigen and present it on its cell surface for recognition of the other immune cells. DCs are classified into four types which include Langerhans, interstitial, myeloid, and lymphoid dendritic cells. Each DC arises from different haemopoietic lineage through different ways and locations(Iwasaki 2007). DCs from bone marrow progenitors circulate in blood as immature precursors prior to migration into peripheral tissues. These cells are characterized by high endocytic activity, low T-cell activation potential, low vaculolar proton pump, high endosomal/lysosomal pH, high levels of cystatin and the cell surface MHC class II is rapidly endocytosed. This immature dendritic move around pathogen environment by pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and when it comes in contact with presentable antigen they mature and move to the lymph node(Vanhoutte, Breuilh et al.). The pathogen is phagocytised and degraded into small peptides and presents those fragments on their cell surface using MHC molecules. Simultaneously, they also up-regulate cell-surface receptors that act as co-receptors for T-cell activation such as CD80, CD86, and CD40 which enhances their ability to activate T-cells. The actual immune response is initiated in secondary lymphoid organs where naÃ¯ve T lymphocytes encounter DCs that present antigens taken up in peripheral tissues. Therefore, DCs plays an interface between the foreign tissue-specific antigens and T lymphocytes, and are the key players in the regulation of cell-mediated immunity(Sallusto and Lanzavecchia 2002; Steinman 2007)
Immature DC is efficient in capturing Ag in different Pathways (a) Fluid phase pinocytosis where large volume of fluid is continuously internalized and it is non- specific uptake of antigens. In micropinocytosis fluid is taken in by formation of small Vesicles of 0.1µM through clathrin coated pits. Macropinocytosis uptakes large fluid vesicles in the form of macropinosome of 1-3µM by membrane ruffling driven by actin cytoskeleton.(b) receptor-mediated endocytosis involving C-type lectin receptors like mannose receptor, DEC-205 or FcÎ³ receptor type I (CD64), type II (CD32) and scavenger receptors (CD36) involved in uptake of immune complexes or opsonized particles. (c) phagocytosis of particles such as latex beads, apoptotic and necrotic cell fragments (involving CD36 and Î±vÎ²3 or Î±vÎ²5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major. DCs can also internalize the peptide loaded heat shock proteins that bind to gp96 and Hsp70 from tumour cell or infected cells.(Sallusto, Cella et al. 1995; Banchereau, Briere et al. 2000)
Once the immature DC captures antigen many signals play their role in DCs maturation. They are (1) Pathogen related molecules such as LPS, Bacterial DNA, dsRNA (2) The local microenvironment balance between proinflammatory and anti-inflammatory signal which includes IL 1Î², TNF, IL-6, IL-10, TGF-Î² and PGE2 (3) Microbial product sensed through TLR (4) T-cell derived signals(West, Wallin et al. 2004). The maturation is a continuous process initiated from the periphery on capturing Ag till DC interacts with naive T cell in the lymphoid organs. During maturation process there is loss of endocytic/phacocytic receptor, up-regulation of co-stimulatory (CD40, CD58, CD80 and CD86) molecules, acquirement of fast cellular morbility, cytoskeleton reorganization by Cdc42/Rac-binding motif of Wasp, actin remodelling by actin-bundling protein p55 fascin, calcium-dependent (c-type) lectin DC immunoreceptor, up-regulation of DC-lysosome- associated membrane protein, increased surface class 11 molecules due to increase in biosynthesis and reduction of internalization. Therefore, stimuli such as TLR and inflammatory cytokines change immature DC into matured once which are specialized in T-cell stimulation(Drutman and Trombetta 2010).
Mature DCs along with Ag subsequently migrate and drain to the lymph node by control of various ligands up-regulated on them. Immature DCs use specific inflammatory chemokine receptor-ligand pathways such as CCR2-CCL2, CCR5-CCL5 and CCR6-CCL20. When DCs mature this chemokine pathway becomes down-regulated and up-regulates CCR7 which binds to two ligands (1) CCL19 which is expressed by stromal cells and mature DCs in the T cell zone (2) CCL21 which is produced by endothelial cells of lymphatic vessels, High Endothelial Venules (HEV) and by stomal cells in T cell zone. These chemokines attract CCR7+ mature DCs into lymphatic node. CCR7+ naive and memory T cells leak through HEV and encounters the T cell area of antigen stimulating lymph nodes.(Martín-Fontecha, Sebastiani et al. 2003; Alvarez, Vollmann et al. 2008)
PROCESSING AND PRESENTATION OF ANTIGEN
MHC CLASS 11
Exogenous soluble and particulate Ags captured by immature DCs are targeted to MHC class II compartments. Immature DCs accumulate MHC class II-rich compartments (MIICs), which are MHC class II molecules in lysosome-related intracellular compartments. The Ag is directed towards MIICs containing HLA-DM which promotes catalytic removal of invariant chain peptide and enhances peptide binding to MHC class II molecules. In absence of invariant chain, Ag and macromolecules have access to acidic prelysosomal M11Cs where, MHC class 11-Ii chain accumulates. The Ii degradation is regulated by the ratio of the cathepsin S and its endogenous inhibitor cystatin C. When DC matures cystatin C down-regulates and cathepin S activity increases which leads to Ii degradation. This allows the peptide-loaded class 11 molecules to be loaded on the surface. Immature DCs internalises class II molecules but on maturation or inflammatory stimuli it leads to a burst of class II synthesis and translocation of MHC II-peptide complexes to the cell surface. Here, they remain stable for days and are available for recognition by CD4+ T cells.
MHC CLASS 1
Intracellular antigens are produced by virus and the cytosolic protein is degraded. The peptides formed are loaded on a newly synthesised MHC class 1 molecule within the endoplasmic reticulum. The pathogen is first digested in the cytosol through ATP dependent proteolytic system. DC matures and up regulates expression of peptide loading complex (PLC) which consists of TAP, TAPASIN. Erp57, calreticulin and MHC class 1 molecule. Digestion can be improved by immunoproteosome which has a unique subunit of Low Molecular Weight proteins (LMP) and DCs also produces di ubiquitin which is efficient in Ag processing. These ubiquitinilated proteins are directed towards the proteasome where the protein is cleaved into peptides. The peptides are then translocated to Endoplasmic Reticulam (ER) by ATP dependant Transporter associated with Antigen Processing (TAP1/2). Tapasin a type 1 transmembrane glycoprotein which has ER retention signal co-immunoprecipitates with TAP. It is essential for peptide loading of MHC 1 molecule and allowing the antigenic peptide to be coupled to an MHC class 1 to generate CD8+ cytotoxic killer cells. MHC class I molecules generally present peptide antigens derived from endogenously synthesized proteins(Hansen and Bouvier 2009). Fig 1 shows about the antigen presentation in MHC 1, MHC 11 and cross presentation.
Cross presentation is a process of cross priming where, certain DCs process and present extracellular antigens to MHC class 1 to stimulate naive cytotoxic CD8+ cells. Endosomal compartments contain endopeptidase such as cathepsin S which plays a major role in cross presentation. The peptides are loaded into class 1 MHC molecule in post golgi compartments. This process is very necessary for immunity against tumours and viruses that do not infect the DCs. It is also required for induction of cytotoxic immunity by vaccination with protein antigens, for example tumour vaccination.(Ackerman and Cresswell 2004).
DCs have evolved to identify danger represented either as tissue damage or as a microbial invasion. Dendritic cells rapidly differentiate when they contact pathogen by range of stimuli and these stimuli trigger innate response that consists of numerous cytokines and chemokines. It is still a mystery how dendritic cells react so vigorously and how their rapid innate responses can be turned into more prolonged adaptive responses, including memory cells. A future research will explore the events that take place after dendritic cells and T cells begin to interact. Dendritic cells start to express cytokines and use other molecules such as CD40 and CD70 to generate strong adaptive resistance. Dendritic Cell Therapy or so-called Dendritic Cell vaccine is a newly emerging and potent form of immune therapy used to treat cancer, AIDS and other serious conditions. Although DCs are potent cells to harness the body's immune response they are not present in adequate quantity. Therefore in DC therapy blood cells are harvested from patients and cultured to produce DCs. This is given back to patients in order to allow massive dendritic participation in optimally activating the immune system. Using cross presentation a novel dendritic cell (DC)-based vaccine can be found by inducing antigen-specific CD8+ T cell responses. Though DC was recently found more research on it may open new areas of science and medicine.