Cross-presentation

Cross-presentation is the ability of certain antigen-presenting cells to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and viruses that do not readily infect antigen-presenting cells, but rather intracellular tumors and viruses that infect peripheral tissue cells. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination. Cross-presentation is the ability of certain antigen-presenting cells to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and viruses that do not readily infect antigen-presenting cells, but rather intracellular tumors and viruses that infect peripheral tissue cells. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination. Cross-presentation is of particular importance, because it permits the presentation of exogenous antigens, which are normally presented by MHC II on the surface of dendritic cells, to also be presented through the MHC I pathway. The MHC I pathway is normally used to present endogenous antigens that have infected a particular cell. However, cross presenting cells are able to utilize the MHC I pathway in order to remain uninfected, while still triggering an adaptive immune response of activated cytotoxic CD8+ T cells against infected peripheral tissue cells. The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of grafted cells carrying foreign minor histocompatibility (MHC) molecules. This resulted in a CD8+ T cell response induced by antigen-presenting cells of the recipient against the foreign MHC cells. Because of this, Bevan implied that these antigen presenting cells must have engulfed and cross presented these foreign MHC cells to host cytotoxic CD8+ cells, thus triggering an adaptive immune response against the grafted tissue. This observation was termed 'cross-priming'. Later, there had been much controversy about cross-presentation, which now is believed to have been due to particularities and limitations of some experimental systems used. Although the primary and most efficient cross presenting cells are dendritic cells, however, macrophages, B lymphocytes and sinusoidal endothelial cells have also been observed to cross present antigens in vivo and in vitro. However, in vivo dendritic cells have been found to be the most efficient and common antigen presenting cells to cross present antigens in MHC I molecules. There are two dendritic cells subtypes; plasmacytoid (pDC) and myeloid (mDC) dendritic cells. pDCs are found within the blood and are able to cross present antigens directly or from neighboring apoptotic cells, but the main physiological significance of pDCs is the secretion of type I IFN in response to bacterial infections. mDCs are categorized as migratory DCs, resident DCs, Langerhans cells, and inflammatory dendritic cells. All mDCs have specialized functions and secretory factors, but they are all still able to cross present antigens in order to activate cytotoxic CD8+ T cells. There are many factors that determine cross presentation function such as antigen uptake and processing mechanism, as well as environmental signals and activation of cross presenting dendritic cells. The activation of cross presenting dendritic cells is dependent on stimulation by CD4+ T helper cells. The co-stimulatory molecule CD40/CD40L along with the danger presence of an exogenous antigen are catalysts for dendritic cell licensing, and thus the cross presentation and activation of naive CD8+ cytotoxic T cells. In addition to solid structure uptake, dendritic cell phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross-presentation pathway instead of the MHC Class II pathway.However, there is still uncertainty in regard to a mechanistic pathway for cross presentation within an antigen presenting cell. Currently, there are two main pathways proposed, cytosolic and vacuolar. The vacuolar pathway is initiated through the endocytosis of an extracellular antigen by a dendritic cell. Endocytosis results in the formation of a phagocytic vesicle, where an increasingly acidic environment along with the activation of enzymes such as lysosomal proteases triggers the degradation of antigen into peptides. The peptides can then be loaded onto MHC I binding grooves within the phagosome. It is unclear whether the MHC I molecule is being exported from the endoplasmic reticulum before peptide loading, or is being recycled from the cell membrane prior to peptide loading. Once the exogenous antigen peptide is loaded onto the MHC class I molecule, the complex is exported to the cell surface for antigen cross presentation presentation. There is also evidence that suggest that cross-presentation requires a separate pathway in a proportion of CD8(+) dendritic cells that are able to cross-present. This pathway is called the cytosolic diversion pathway. Similarly to the vacuolar pathway, antigens are taken into the cell through endocytosis. Antigen proteins are transported out of this compartment into the cytoplasm by unknown mechanisms. Within the cytoplasm, exogenous antigens are processed by the proteasome and degraded into peptides. These processed peptides can either be transported by the TAP transporter into the endoplasmic reticulum, or back into the same endosome for loading onto MHC class I complexes,. It is believed that MHC I loading occurs both in the ER as well as phagocytic vesicles such as an endosome in the cytosolic pathway. For MHC class I loading within the Endoplasmic Reticulum, exogenous antigen peptides are loaded onto MHC class I molecules with the help of the peptide loading complex and chaperone proteins such as beta-2 microglobulin, ERAP, tapapsin, and calreticulin. After antigen peptide loading, the MHC molecule is transported out of the ER, through the Golgi complex, and then onto the cell surface for cross presentation.