Organisms are constantly invaded by pathogens such as viruses. Our immune system kicks in to immediately fight off these pathogens. The innate nonspecific immune response is triggered first, followed by the adaptive or acquired immune response. In this second defense response, specialized cytotoxic T cells, known as killer T cells, destroy cells in the body that have been infected and thus prevent the damage from spreading. Man has a repertoire of some million T lymphocyte clones of varying specificity to counter the multitude existing infectious agents. But how do killer T cells know where the risk is coming from? How do they recognize that something is wrong inside a cell where viruses are hiding? They can’t just peek inside.
At this point, the antigen treatment enters involved. The process can be compared to making a traffic sign. The molecular barcode is “processed” or assembled in the cell – in the endoplasmic reticulum, to be precise. Special molecules are used in its manufacture, the MHC class I molecules. They are loaded with information about the viral invader in a molecular machine, the peptide loading complex (PLC). This information is made up of peptides, fragments of the protein foreign to the organism. These fragments also contain epitopes, the molecular segments that trigger a specific immune response. During the loading process, an MHC I-peptide epitope complex is thus formed, and this is the road sign which is then transported to the cell floor and presented in a form readily available to killer T cells — one could almost say that it is handed to them on a silver platter. Chaperones, special accessory proteins that aid in the accurate folding of proteins with complex structures in cells, also play a vital role.
Chaperones that support processing of the antigen are calreticulin, ERp57 and tapasine. But how do they work together? And what is their importance for antigen processing? An answer has just been provided by a study conducted by the Goethe University of Frankfurt and the University of Oxford and published in Nature Communications. “With this study, we have achieved a breakthrough in our understanding of cellular quality control,” says Professor Robert Tampé, director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic that tends to underlie this quality control process as follows: does not start instantly. It needs 3-5 days to start.” Thus, the sign should not collapse after one day it would be disastrous, because the immune defense cells would then fail to detect the cells infected by a virus. This would mean that they would not destroy these cells and the virus could continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumor cell: the threat would remain undetected. It is therefore imperative that a quality control system is in place.
As the study shows, chaperones are central elements of the process: they give the traffic sign the long-term stability it needs to have through careful selection. By rejecting short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. Chaperones have different jobs in this selection process that is so vital to the adaptive immune response, Tampé explains: “Tapasine acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERP57, on the other hand, are deployed universally.” This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell floor and fulfill their role of guiding killer T cells to the infected or mutated cell.
In which directions does the study point? “We now have a better understanding of which peptides are charged and how this happens now. We can also more reliably predict the dominant peptide epitopes, in other words the stable peptide epitopes that will be selected by the chaperone network. Tampé hopes the new findings will prove useful in developing future vaccines against variants of the virus. They could also facilitate progress on future antitumor therapies. “The two subjects are directly linked. But the applications in tumor therapy are certainly more complex and more long-term.”
Infectious AgentAntigenCellChaperonePeptidProteinImmune SystemVirus