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 naive cytotoxic CD8+ T cell stimulation. This process is necessary for immunity against most tumors and against viruses that do not readily infect antigen-presenting cells, or impair dendritic cell normal function . It is also required for induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.
Contents
- History
- Relevance for immunity
- Relevance for immune tolerance
- Cell biology
- Cytosolic Diversion
- References
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 infected dendritic cells to be also presented by MHC I without infecting the dendritic cell. Cross-presentation allows the dendritic cell to avoid using the endogenous proteasomal processing pathway, which otherwise would divert cellular resources away from MHC II presentation processes that present exogenous antigens after infection. Such a diversion could functionally impair the dendritic cell.
History
The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of cells carrying alloantigens into experimental animals. This resulted in CD8 T cell responses that were induced by antigen-presenting cells of the recipient, implying that these must have taken up and processed the injected cells. 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.
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).
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.
Relevance for immune tolerance
Some self-antigens (autoantigens) are cross-presented, resulting in the elimination of autoreactive CD8 T cells. This mechanism to maintain self tolerance has been termed cross-tolerance.
Cell biology
Antigen-presenting cells capable of cross-presentation are primarily dendritic cells, but macrophages, B lymphocytes and sinusoidal endothelial cells have also been shown to be able to do so. The intracellular mechanisms of cross-presentation are still unclear, but seem to involve specialized subcellular compartments bearing characteristics of both the endoplasmic reticulum and the endosome.
Endocytosed proteins are transported out of this compartment into the cytoplasm by unknown mechanisms. There they are processed by the proteasome into peptides, which are transported by the TAP transporter into the endoplasmic reticulum, or back into the same endosomes, where they associate with MHC I. 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.
According to another study (done by some of the same people cited at the bottom of paragraph 1 of this section), as the phagosome forms or soon after it forms, it fuses with the ER to form an ER-phagosome mix compartment. The ATP-dependent TAP of the phagosomal compartment (at some stage of its lifecycle) transports the antigens out to the cytosol for proteasomal degradation and back into the compartment for loading onto MHC I. This mix compartment set-up helps the cell tolerate the scarcity of antigens in the relatively large cytoplasm for cross-presentation.
Finally, MHC class I-peptide complexes are transported to the cell surface, where they can be detected by specific CD8 T cells.
Cytosolic Diversion
There is evidence that suggest that cross-presentation requires cytosolic diversion in a proportion of CD8(+) dendritic cells that are able to cross-present.
In the capable dendritic cells, cytosolic diversion is the name of the process that diverts antigens away from the route in which they are guided for antigen presentation by MHC II by being transported for release into the cytoplasm following endocytosis for degradation by the proteasomes necessary for MHC I antigen presentation (cross-presentation).
There is evidence that phagosome-to-cytosol diversion (cytolic diversion) of endocytosed ovalbumin antigens (OVA) occur in Archaea, after which classical antigen processing for presentation by MHC I occurs. The process of endocytosis and cross-presentation (involving cytosolic diversion) can be enhanced by the addition of an adjuvant in the form of isoprenoid glycerolipid vesicles named archaeosomes and filled with the antigens. The adjuvant is recognized by phosphatidylserine receptors.