Lysosomal Activity Changes as Dendritic Cells Mature

Their findings were published in the March 7, 2003, issue of Science.

Dendritic cells are the most potent antigen-presenting cells involved in host defense. All immunogenic and tolerogenic responses are initiated upon the recognition of antigen presented by mature dendritic cells, playing an important role in the immune response in cancer and autoimmune diseases.

In response to a variety of stimuli, dendritic cells transform from immature cells specialized for antigen capture into mature cells specialized for T cell stimulation. The physiologic basis of this maturation process was not well understood.

In the current study, investigators from Yale University's Ludwig Cancer Institute (New Haven, CT, USA; www.yale.edu) showed that dendritic cell maturation was accompanied by an acidic shift in lysosomes that favored the production of immune stimulating molecules. 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. However, in mature dendritic cells antigens are sequestered in the lysosomes and then degraded into peptide fragments that are 10-to-15 amino acids in length. These fragments then bind to other molecules, which transport them from lysosomes to the surface of cells.

"Despite rather unfavorable conditions, mature dendritic cells are able to use their lysosomes to warn the immune system,” explained senior author Dr. Ira Mellman, a researcher in the department of cell biology at Yale University School of Medicine. "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.”

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