Importance of cross-presentation of antigens by antigen-presenting cells

In this article, I briefly explain how the antigen-presenting cells cross-present antigens.

Table of Contents

Types of antigens

There are different pathways employed by the immune system for eradicating intracellular and extracellular pathogens. The antigens generated within the cell are known as endogenous antigens. These antigens are processed by the cytosolic or endogenous pathway and presented on the cell membrane with class-I MHC molecules. The antigens that emerge from the extracellular environment are known as exogenous antigens. These are processed by the exogenous pathway and presented on the cell membrane with class-II MHC molecules.

Cross-presentation of antigens

Cross-presentation of antigens is the unconventional way of processing and presentation of antigens by MHC molecules. It is experimentally and clinically observed that exogenous antigens can be presented by the class-I MHC molecules. The class-II MHC molecules present endogenous antigens. This phenomenon was first reported by Michael Bevan and later elaborated by Peter Creswell and colleagues.

Cross-presentation of antigens is a phenomenon that requires the antigens to be acquired from extracellular sources. After that, they are processed through the exogenous pathway. Finally, they are presented with class-II MHC but redirected to a class-I peptide loading pathway.

In autophagy, the cytosolic components are enclosed in vesicle traffic through compartments of lysosome. Finally, cytosolic peptides are presented by the class-II MHC molecules.

Extracellular antigens are internalized by professional antigen-presenting cells. These antigens are then processed by the conventional exogenous pathway and presented with class-II MHC molecules.

The co-stimulatory molecules expressed by the antigen-presenting cells activate the T helper cell response by the engagement of CD4⁺ T_H cells with the class-II MHC-peptide complexes.

Generally, the infected cells process and present cytosolic peptides through the endogenous pathway. However, the infected cells can not activate the naïve CD8⁺ T cells without expressing the costimulatory molecules.

It will be difficult for the immune system to activate the CD8⁺ T cells for the elimination of intracellular microbes unless a professional antigen-presenting cell gets infected. In this predicament, cross-presentation combines the exogenous and endogenous pathways. With this combination, certain antigen-presenting cells will divert the antigen obtained by endocytosis to another pathway. This pathway leads to class-I MHC peptide presentation to CD8⁺ T cells.

This type of activation of naïve CD8⁺ T cells is called cross-priming. When the antigen-presenting cells are not activated, it induces tolerance in the CD8⁺ T cells, known as cross-tolerance.

Dendritic cells cross-present exogenous antigens through class-I MHC molecules

The dendritic cells residing in secondary lymphoid organs are the most potent cross-presenting among other dendritic cells.

The dendritic cells pick up antigens from extracellular resources like from migrating antigen-presenting cells or from dying infected cells. Somehow, these exogenous antigens can gain access to the endogenous presentation pathway in the process of cross-presentation. This leads to peptide presentation with the class-I MHC and engagement with the CD8⁺ T cells.

Two possibilities for cross-presenting cells have been proposed. One of which describes the possession of special antigen-processing machinery by cross-presenting cells. This allows the packing of exogenously derived peptides onto class-I MHC molecules.

According to another theory, internalized antigens can be sent to an organelle through specialized endocytosis machinery. Then, peptides from those antigens are stocked onto class-I MHC molecules through the conventional method.

In some cases, it has been found that cross-presented antigens from external sources enter the cytoplasm. In the early 1990s, it was believed that bead-conjugated antigens caught by cross-presenting dendritic cells could reach the cytosol of these cells.

M.L. Lin and colleagues later discovered that exogenously added cytochrome c could induce apoptosis in cross-presenting dendritic cells. It is because cytochrome c when present in the cytosol, causes programmed cell death.

Role of TAP molecules and receptors

The presence of TAP (transporter associated with antigen processing) molecules in endocytic membranes causes the movement of endocytosed proteins out of endocytosed compartments into the cytosol. However, it has been seen that some antigens independent of TAP molecules are cross-presented to MHC molecules, thus showing numerous mechanisms behind this.

Ligand binding receptors to pattern recognition receptors like toll-like receptors are responsible for the maturation of dendritic cells. These receptors can trigger the transport of class-I MHC molecules from intracellular apparatus to these antigen-presenting cells.

Apart from these mechanisms, the host has a great advantage in the ability of dendritic cells for cross-presentation of antigens from external sources. These antigen-presenting cells catch antigens from dying cells or the extracellular environment. Then, process them and activate cytotoxic lymphocytes (CTLs), which attack infected cells.

Regulation of cross-presentation

Before the process of cross-presenting antigens, dendritic cells first activate them and get them licensed by antigen-specific T helper cells. Dendritic cells first internalize the antigens and process them through the exogenous pathway. After processing the antigens, dendritic cells present these antigens to CD4⁺ T_H cells through class-II MHC molecules (Figure 1). In this way, activating these T helper cells through the engagement of CD40 and CD40L.

These activated T_H cells serve as an intermediate to activate CTL responses. The activated T helper cells induce the expression of costimulatory molecules and stimulatory cytokines in dendritic cells. In this way, these activated T_H cells give license to dendritic cells. Thus, dendritic cells can cross-present internalized antigens through class-I MHC molecules. As a result, it causes the activation of the naïve CD8⁺ T_C cells (Figure 2).

Thus, this licensing by a T helper cell could aid in avoiding the interaction of CTLs with nonpathogenic antigens or self-proteins. In this case, if any inactivated and unlicensed dendritic cells cross-presenting antigens lack costimulatory molecules can induce tolerance. They induce tolerance in the CD8⁺T cells they come across. This would help maintain self-tolerance in dendritic cells.

Conclusion

Cross-presentation of antigens is not the conventional way of processing and presentation of antigens by MHC molecules. However, there is the importance of cross-presentation of antigens by antigen-presenting cells. Exogenous antigens can be presented by class-I MHC molecules, whereas endogenous antigens can be presented by class-II MHC molecules.

Cross-presentation of antigens is a phenomenon, which requires the antigens to be acquired from extracellular sources. After that, they are processed through the exogenous pathway. Finally, they are presented with the class-II MHC but redirected to a class-I peptide loading pathway.

The dendritic cells cross-present exogenous antigens through class-I MHC molecules. Before the process of cross-presenting antigens, dendritic cells first activate them and get them licensed by antigen-specific T helper cells. The licensing by a T helper cell could aid in avoiding the interaction of CTLs (cytotoxic lymphocytes) with nonpathogenic antigens or self-proteins.