Cross-presentation

The term cross-presentation (or cross-priming) denotes 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). This process is necessary for immunity against most tumors and against viruses that do not infect antigen-presenting cells.^[1][2]

It is also required for induction of cytotoxic immunity by vaccination with protein antigens, for example in tumor vaccination.^[3]

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History

The first evidence of cross-presentation was reported 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”.^[4]

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.^[5]

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,..), bacteria (Listeria, Salmonella, E.coli,…) and tumors (Brain, pancreas, melanoma, leukemia,..).^[6][7]

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

Also 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.^[8]

Cell biology

Antigen-presenting cells capable of cross-presentation are primarily dendritic cells,^[9][10] but also macrophages, B lymphocytes and liver sinusoidal endothelial cells have 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.^[11][12]

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, where they associate with MHC class I molecules. ^[13][11]

Finally, MHC class I - peptide complexes are transported to the cell surface, where they can be detected by specific CD8 T cells.

References