Cross-presentation

The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of grafted cells carrying foreign minor histocompatibility (MiHA) molecules. This resulted in a CD8+ T cell response induced by antigen-presenting cells of the recipient against the foreign MiHA cells. Because of this, Bevan implied that these antigen presenting cells must have engulfed and cross presented these foreign MiHA cells to host cytotoxic CD8+ cells, thus triggering an adaptive immune response against the grafted tissue. This observation was termed "cross-priming". ==Cross-presenting cells==

The primary and most efficient cross-presenting cells are dendritic cells, though 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. 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. ==Vacuolar and cytosolic diversion==

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. 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 ER, 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, tapasin, 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. It appears that both pathways are able to occur within an antigen-presenting cell, and may be influenced by environmental factors such as proteasome and phagocytic inhibitors. == Relevance for immunity ==

Cross-presentation has been shown to play a role in the immune defense against many viruses (herpesvirus, influenzavirus, CMV, EBV, SIV, papillomavirus, and others), bacteria (listeria, salmonella, E. coli, M. tuberculosis, and others) and tumors (brain, pancreas, melanoma, leukemia, and others). Even though many viruses can inhibit and degrade dendritic cell activity, cross-presenting dendritic cells that are unaffected by the virus are able to intake the infected peripheral cell and still cross present the exogenous antigen to cytotoxic T cells. The action of cross priming can bolster immunity against antigens that target intracellular peripheral tissues that are unable to be mediated by antibodies produced through B cells. Also, cross-priming avoids viral immune evasion strategies, such as suppression of antigen processing. Consequently, immune responses against viruses that are able to do so, such as herpes viruses, are largely dependent on cross-presentation for a successful immune response. Overall, cross presentation aids in facilitating an adaptive immune response against intracellular viruses and tumor cells. Dendritic cell-dependent cross-presentation also has implications for cancer immunotherapy vaccines. The injection of anti-tumor specific vaccines can be targeted to specific dendritic cell subsets within peripheral skin tissues, such as migratory dendritic cells and Langerhans cells. After vaccine induced activation, dendritic cells are able to migrate to lymph nodes and activate CD4+ T helper cells as well as cross prime CD8+ T cytotoxic cells. This mass generation of activated tumor specific CD8+ T cells increases anti-tumor immunity, and is also able to overcome many of the immune suppressive effects of tumor cells. ==Relevance for immune tolerance==

Cross-presenting dendritic cells have a significant impact on the promotion of central and peripheral immune tolerance. In central tolerance, dendritic cells are present within the thymus, or the location of T cell development and maturation. Thymic dendritic cells can intake dead medullary thymic epithelial cells, and cross present "self" peptides on MHC class I as a negative selection check on cytotoxic T cells that have a high affinity for self peptides. ==References==