How Dendritic Cells Grow Up to Take on Foreign Invaders

Acting as the body's sentinels, dendritic cells are constantly on the look out for foreign invaders, seeking to capture and turn over the enemy to T-cells, the primary enforcer of an immune system attack. For reasons that had yet to be explained, only mature dendritic cells process and accumulate these threatening molecules with any great affect.

This unique function has fueled an interest in using activated dendritic cells to fight cancer and other diseases. Investigators at the Ludwig Institute for Cancer Research have potentially aided these efforts by discovering just how mature dendritic cells become so efficient at alerting the immune system to threats. The key, according to a study published in the current issue of Science, appears to come from the general awakening of lysosomes, a type of waste bucket cell that remains largely unused if not galvanized into action.

"Despite rather unfavorable conditions, mature dendritic cells are able to use their lysosomes to warn the immune system," said the study's lead author, Dr. Ira Mellman, who is with the Department of Cell Biology and Section of Immunobiology at Yale University School of Medicine, and an affiliate at the Ludwig Institute for Cancer Research. "For 50 years, we have been taught that lysosomes simply degrade all protein they encounter, a situation which would prevent the formation of the large protein fragments required to generate immunity. Dendritic cells have contrived a way around the conventional view of lysosomes by controlling their activities."

In general, lysosomes quickly destroy internalized proteins from bacteria, viruses, or cancer cells and then convert them into individual amino acids that are too small to be recognized by the immune system. Immature dendritic cells act as antigen prospectors and collectors, however. They circulate throughout the body looking for foreign invaders and accumulate them inside, allowing them to reside in lysosomes for days at a time apparently unscathed.

Once exposed to the right signals, dendritic cells mature and adopt special characteristics that allow them to degrade their accumulated antigens into peptide fragments that are 10-to-15 amino acids in length. These fragments then bind to other molecules which ferry them from lysosomes to the surface of cells, setting off alarms.

The probable cause of this, Dr. Mellman's team discovered, was that lysosomes found in mature dendritic cells were consistently more acidic than those found in the immature ones. Based on a range of different experiments, his team found that dendritic cell maturation is accompanied by an acidic shift in lysosomes that favors the production of immune stimulating molecules.

"The fact that lysosomes appear developmentally controlled would explain a key feature of why dendritic cells are so good at what they do," said Dr. Mellman.

This insight is already being put to use in harnessing the power of dendritic cells in creating new vaccines for cancer and other diseases.