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Dendritic cells are found in many tissues and represent the main antigen-presenting cells (APCs) which interact with T-cell receptors. They uptake a wide variety of exogenous antigens via macropinocytosis, phagocytosis, and clathrin-mediated endocytosis and present the processed antigens as peptides to T cells. The exogenous antigens from dendritic cells (DCs) are processed and presented via both histocompatibility complex (MHC) class I and class II pathways. Cross-presentation of antigens is associated with the MHC class I pathway and is implicated in the generation of an immune response against viral infection and tumors.
After antigens enter the human body, they are captured by antigen-presenting cells (APCs) via endocytosis or phagocytosis and degraded into peptides. B lymphocytes, dendritic cells (DCs), macrophages, and thymic epithelial cells are APCs, and they mainly present exogenous antigens to both histocompatibility complex (MHC) class I and class II (Coico and Sunshine, 2009, Harding and Song, 1994).
Most DCs are found in Langerhans skin cells and ingest antigens by macropinocytosis and phagocytosis (Coico and Sunshine, 2009, Steinman and Banchereau, 2007). Following the ingestion of antigens, the proteins are processed into peptides which are loaded onto MHC-I and MHC-II molecules inside the host cell and presented to T cells (Coico and Sunshine, 2009). MHC-I molecules bind peptides from the cytoplasmic compartment (endogenous), whereas MHC-II molecules bind peptides from outside the cell (exogenous) (Coico and Sunshine, 2009). Furthermore, DCs have been proposed to be able to present exogenous antigens to MHC-I molecules via cross-presentation (Mellman and Steinman, 2001). This review will mainly focus on DCs capture, processing and presentation of exogenous antigen.
Maturation and uptake of exogenous antigens by dendritic cells
Most immature DCs are found in peripheral tissues, and they uptake antigens by macropinocytosis, phagocytosis, and clathrin-mediated endocytosis (Young et al., 2007, Mellman and Steinman, 2001). In macropinocytosis, large amounts of fluid are engulfed in single vesicles. Phagocytes ingest large particles such as dying cells, bacteria and viruses and then fuse with the lysosome and turn into a phagosome. Clathrin-mediated endocytosis internalizes extracellular molecules forming a plasma membrane vesicles which contain proteins and receptors (Brode and MacAry, 2004).
The immuture DCs express many Toll-like receptors and C-type lectin receptors (CLRs) in order to response microbial components and induce the synthesis of cytokines such as interlukine-1 (IL-1) and type 1 interferons (Steinman and Banchereau, 2007, DeFranco et al., 2007). Some inflammatory chemokine receptors such as CCR1, CCR2 and CCR5 are also expressed by tissue-resident DCs and leads DCs to site of infection (DeFranco et al., 2007).When the immature DCs receive signals from Toll-like receptors (TLRs), C-type lectin receptors, infection, inflammation cytokines, and natural killer (NK) cells, they are induced to become mature DCs and migrate to secondary lymphoid organs (Trombetta and Mellman, 2005, Figdor et al., 2002).
Immature DCs are highly phagocytic activity and produce low levels of MHC class I and class II molecules. However, mature DCs downregulate endocytosis, but they produce high levels of MHC molecule:peptide complexes and have the ability to present antigens to T cells (Mellman and Steinman, 2001). The mature DCs migrate from peripheral tissues to local lymphoid tissues where they express co-stimulate molecules, B7 molecules, and active naÃ¯ve T cells (DeFranco et al., 2007). Therefore, DCs uptake of antigens plays a key role in the innate and adaptive immune system.
Dendritic cells capture exogenous antigens and process via MHC-II pathway
MHC class II molecules are constitutively expressed by APCs and usually present peptides from exogenous antigens to CD4+ T cells via the endocytic route (Heath and Carbone, 2001). Exogenous antigens such as bacteria or viruses are engulfed by immature DCs via endocytosis or phagocytosis, and the foreign antigens are degraded within endosomal or lysosomal vesicles containing highly acidic compartment (pH around 4.0) (Coico and Sunshine, 2009). The vesicles contain cathepsins which are degradation enzymes, such as proteases, which degrade foreign proteins into peptide fragments (Coico and Sunshine, 2009).
In the immature DCs stage, DCs have a lower ability to degrade foreign proteins because cathepsin S (cat S) protease activity is inhibited by high level Cystatin C which limits the MHC-II associated invariant chain (li) processing (Guermonprez et al., 2002, Pierre and Mellman, 1998). Therefore, immature DCs have an increased capacity to endocytose but a lower ability to load peptides on MHC-II molecules.
In the early stage of DCs endocytosis, MHC-II molecules are synthesized by ribosomes on the rough endoplasmic reticulum (ER). The Î± and Î² chains of MHC-II molecules are synthesized individually in the ER and are associated to a Ii chain. The Ii chain works as a chaperone on the newly formed MHC-II molecules, and allows the transport of MHC-II molecules from the ER to the Golgi apparatus (Fig 1.) (Villadangos et al., 2001, Coico and Sunshine, 2009) . When the newly formed MHC-II molecules proceed to endosomes and lysosomes, the Ii chain is degraded by proteolytic enzymes in the highly acid vesicles and produce Class II-associated Invaraint Polypeptide (CLIP) on the MHC-II groove (Fig 1 & 3) (Heath and Carbone, 2001, Imai et al., 2005). The MHC-II molecules bind peptides by exchanging CLIP , and then the mature DCs with MHC II: peptide complex present peptides to CD4+ T cells (Fig 1.) (Coico and Sunshine, 2009). As a result, the mature DCs have reduced ability to uptake antigens but upregulate the generation of MHC II: peptide complex due to high protease activity and low level of Cystatin C (Heath and Carbone, 2001).
Fig 1. Uptake of exogenous antigens and processing via the MHC-II pathway. Ii = invariant chain; CLIP = fragment of Ii bound to MHC class II groove. Figure taken from Coico and Sunshine, 2009
Dendritic cells present exogenous antigens to MHC-I via cross-presentation
The MHC-I pathway involves processing and presentation of endogenous antigens, such as virus-infected host cells, in the cytoplasm (Coico and Sunshine, 2009). The antigens are degraded into peptides via proteasomal proteolysis, and the peptides are then transported into the ER via the transport of antigen processing (TAP) molecules and loaded onto MHC-I molecules. MHC-I:peptide complexes in the ER are transported to the Golgi apparatus and present antigens to cytotoxic CD8+ T lymphocytes (CTLs) on the cell surface (Fig 2.) (Heath and Carbone, 2001, Coico and Sunshine, 2009). However, not every DC can be infected by viruses. Therefore, immature DCs can also uptake exogenous or dying cells and present peptides to CD8+ T cells via cross-presentation (Mellman and Steinman, 2001, Steinman and Banchereau, 2007).
Fig 2. Presentation of endogenous antigens via MHC-I classical pathway. Figure taken from Coico and Sunshine, 2009
During cross-presentation, exogenous antigens such as apoptotic cells are engulfed by DCs via phagocytosis and macropinocytosis. The exogenous antigens in the endosome are translocated into the cytosol of DCs. The cytosolic antigens are degraded via the proteasome and cut into peptides. The antigen peptides are transferred by TAP from ER to be loaded onto MHC-I molecules (Lin et al., 2008, Fonteneau et al., 2003). Subsequently, MHC-I:peptides expressed on DCs transferred to the cell surface interact with naive CD8+ T cells and activate cytotoxic CD8+ T cells to kill the infected host cells (Fig 3.) (Heath and Carbone, 2001).
Therefore, DCs not only process exogenous antigens via MHC-II pathway but also MHC-I by cross-presentation (Coico and Sunshine, 2009). Furthermore, the process of cross-presentation has been proposed to play an important role to increase host cells capacity to defeat tumour, viral infection and bacterial heat shock proteins (HSPs) have been recognized to be presented by this process (Fonteneau et al., 2003).
Fig 3. Antigens presented via MHC-I and MHC-II molecules. MHC II-Ii, Invariant chain-MHC class II complexes; CLIP , class II-associated invariant-chain peptide; TAP, transporters of antigen-processing; molecules MIIC, MHC II loading compartment; CIIV, MHC II vesicles. Figure taken from Heath and Carbone, 2001
DCs have immature and mature forms. Immature DCs have an ability to capture a wide range of antigens from peripheral tissues via endocytosis or phagocytosis. When they receive danger signals from inflammatory cytokines, Toll-like receptors and chemokines, they start to migrate to lymphoid organs and become mature DCs. The mature DCs have distinguished ability to active naÃ¯ve T cells and increase the expression of co-stimulate molecules.
The fundamental abilities of DCs are antigen uptake and T cell activation via antigen process and presentation. Exogenous antigens from DCs are degraded into peptides and bind to MHC-II molecules in the endosome, and then the MHC-II:peptide complexes are transferred to the cell surface allowing them to be presented to CD4+ T cells. In addition, the DCs can also present exogenous antigens to MHC-I molecules via cross-presentation. During cross-presentation, exogenous antigens are transported into the cytoplasm via TAP to be presented to CD8+ T cells and active naive CD8+ T cells. The cross-presentation has been recognized as an important mechanism for human immune response to tumours and viral infection. Therefore, DCs are specialized to capture antigens and degrade (process) the proteins into fragment peptides which are then loaded onto MHC molecules in the host cells. The DCs with MHC:peptide complexes are recognized and presented to T cells. As a result, DCs play an important role in activating naÃ¯ve T cells and therefore play a key role in the innate and adaptive immune response.