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.

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

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”.

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,..), bacteria (Listeria, Salmonella, E.coli,…) and tumors (Brain, pancreas, melanoma, leukemia,..).

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.

Cell biology
Antigen-presenting cells capable of cross-presentation are primarily dendritic cells, 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.

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.

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

Role of CD4 T cell help
There is currently much debate over the role of CD4 T cell help for the CD8 T cell response. It is thought that vigorous CD8 T cell responses and the generation and maintenance of CD8 T cell memory require help by CD4 T cells.

These stimulate dendritic cells by the cell surface molecule CD40 ligand, or directly stimulate CD8 T cells by cytokines such as Interleukin-2.

In the absence of such help, CD8 T cells die upon secondary encounter with antigen.

The involvement of CD4 T helper cells implies that the AIDS virus indirectly compromises antiviral CD8 T cell responses, and may thereby escape immune defense.