How does the immune system isolate and destroy intruders?

Dendritic cells are the body's "watchdogs". They recognize and then degrade pathogens, isolating characteristic fragments that are recognized by the immune system thus triggering targeted responses.

At the Institut Curie, CNRS and Inserm researchers have now discovered how dendritic cells produce these fragments. They have revealed the hitherto unknown role of the NADPH oxidase NOX2 in immune recognition, thus shedding light on how the immune system works and so enhancing our capacity to manipulate and use it therapeutically. This discovery, published in the July 14, 2006 issue of Cell, should help us to fine-tune the immune response in the treatment of certain diseases like cancer.

The body is constantly under attack from outside forces (viruses and bacteria) and sometimes from forces within (cellular abnormalities leading to cancer). Its defensive response is to activate the immune system. There are two types of defense. First, there is innate immunity, which has no memory and so is constantly on the lookout for infectious agents to destroy. Second, there is adaptive immunity, which over time acquires memories of particular pathogens. This requires a "learning" phase in which the dendritic cells degrade pathogenic agents into characteristic fragments, the epitopes, and then present these epitopes to the T and B lymphocytes, thereby initiating immune responses. The pathogen's profile is memorized through this learning process and the next time the same pathogen is encountered the body immediately recognizes it and so is able to respond rapidly.

In innate immune responses, the invader is totally destroyed, a process in which the NADPH oxidase NOX2 plays a central role. In neutrophils, the cells at the heart of innate immune responses, NOX2 ensures the complete destruction of invading pathogens so they are no longer harmful to the body.

In adaptive immune responses, the dendritic cells' challenge is to degrade the pathogen just partially, thus preserving sufficiently representative fragments that can be presented to the T and B lymphocytes. Ariel Savina at the Institut Curie, in the Inserm team of Sebastian Amigorena, has been studying how dendritic cells, the body's "watchdogs", achieve this controlled degradation of pathogens into epitopes. What they have found is that NOX2 is also implicated in adaptive immune responses. Its role in this case contrasts with that in neutrophils. NOX2 regulates the pH in the compartments (phagosomes) of the dendritic cells where pathogens are degraded, thus ensuring suitable acidity. This pH regulation slows the degradation of the pathogens thus avoiding their complete destruction, which allows the dendritic cells to trigger a specific and efficient adaptive immune response.

These new findings shed light on how the immune system works and should help us to optimize one of the most promising approaches to cancer treatment: immunotherapy, in which the immune system is used to destroy tumor cells. The Institut Curie has for many years been participating actively in the development of innovative immunotherapeutic strategies. Two clinical trials are currently under way at the Institut Curie, one in patients with choroidal melanoma and another in cervical cancer patients. The results are expected some time in 2007.


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