Latest insights into how dendritic cells arm T cells to fight disease

As a part of the immune system, dendritic cells are essential for fighting body cells which have degenerated or are infected with a virus. They trigger an immune response by presenting protein fragments, for instance of viruses, to T cells. In so doing, they activate the latter in order that these recognize the fragments as foreign. Certain membrane proteins, MHC-I molecules, enable this process inside dendritic cells. Researchers at Goethe University Frankfurt and its partner institutes have now identified further interaction partners of the protein complex accountable for loading MHC-I molecules in dendritic cells.

The precise or acquired immune system of vertebrates is a robust weapon against pathogens and pathologically altered body cells. Here, T cells play a special role. After activation, they will systematically kill off course cells which have degenerated or are infected with a virus. They carry a receptor on their surface that recognizes small protein fragments – antigens – presented to them by specialized immune cells, including the highly efficient dendritic cells. These are phagocytes (scavenger cells) that patrol through the body in the hunt for infected or degenerated cells, ingest them and degrade them inside a membrane vesicle. During this process, antigens are produced that enable the dendritic cells to bind to MHC-I receptors after which present them on the cell surface.

The antigenic MHC-I molecules remain stable for several days. During this time, their purpose is to activate immature (naïve) T cells and transform them into potent killer cells (cytotoxic T cells). Due to this “armoring function”, dendritic cells constitute a ray of hope for personalized immunotherapy. With the participation of Dr. Christian Schölz from the Max von Pettenkofer Institute in Munich in addition to Professor Reinhold Förster and Professor Ulrich Kalinke from Hannover Medical School, a team led by Professor Robert Tampé from Goethe University Frankfurt has now been capable of show that the protein complex accountable for loading MHC-I molecules in dendritic cells is organized in supramolecular assemblies for particularly efficient antigen presentation.

Like all surface proteins, MHC-I molecules are incorporated into the membrane of the intracellular endoplasmic reticulum (ER) during synthesis. The ER is a system of tubules and sacs contained in the cell, through which the MHC-I molecules are loaded with antigens carried there via a transporter called TAP.

Small vesicles with the loaded MHC-I molecules bud off from the endoplasmic reticulum, migrate to the cell membrane and fuse with it in order that they seem on the cell surface and might interact with T cells. “All body cells with a nucleus present their very own antigens to the immune system,” Tampé explains, “but dendritic cells are those that present the antigens of other cells on MHC-I better of all and in this manner are capable of arm T cells.” It is because dendritic cells have an ER with a very extensive network of tubules and sacs.

For his or her experiments, the researchers examined dendritic cells in an early stage of cell development, often called progenitor cells, allowing them to develop first into immature after which mature dendritic cells. In all three groups of cells, they found an antigenic peptide loading complex composed of TAP, MHC-I and three other proteins: tapasin, ERp57 and calreticulin, folding enzymes (chaperones) that help the three-dimensional structure of MHC-I to form appropriately.

Within the mature dendritic cells, three other proteins further enriched the loading complex: The researchers discovered VAPA and ESYT1 in close proximity, which normally appear at contact sites between the ER and other cell membranes, in addition to BAP31. BAP31 occurs at ER exit sites, that’s, where the vesicles with the folded proteins bud off from the ER. “This result indicates that antigen processing in dendritic cells is more efficient when the loading complex doesn’t operate by itself but works in organized alliances,” says Martina Barends, certainly one of the primary authors of the research paper.

This cooperation with the newly described partners suggests that loading of MHC-I molecules occurs at ER exit sites, which could enable the complexes to succeed in the cell surface particularly quickly. Furthermore, loading complexes at contact sites between the ER and plasma membrane could facilitate direct transport to the cell surface. Tampé is convinced: “This is able to make antigen presentation way more efficient.” The hope now could be that these findings will assist in the event of recent immunization strategies and immunotherapies. “We now have a greater idea of how antigens are produced in dendritic cells that will be used therapeutically,” summarizes Tampé.