Why are cells useful for our body?

The weapons of the immune system: how killer cells differentiate between endogenous and foreign

We are outnumbered in our bodies. Roughly speaking, the human body consists of around 1013 Cells - that's ten trillion, over a thousand times more cells than humans live on this planet. In contrast, there are around 1014 Bacteria that live in and on our body, ten times more than cells in our body. That corresponds to a mass of over a kilo of bacteria that each of us carries around with us. Admittedly, most of these sub-tenants are quite useful contemporaries, without whom we cannot digest our food and who protect us from pathogens. Nevertheless, we are exposed to the risk of being overrun by dangerous microorganisms on a daily basis. The largest organ in our body, the immune system, is there to ward off this danger.

It also has a large number of effective weapons at its disposal, which can be deadly not only for pathogens, but also for the body's own cells. For this reason, it is the job of the immune system to distinguish between friend and foe, between dangerous and harmless. It is not enough to simply regard everything foreign as dangerous and to consider the self to be good in principle. The food in our intestines or the pollen in spring are exogenous substances, but they are not a threat to our body and should therefore not be attacked. If our body attacks such foreign substances anyway, it has fatal consequences, as can be observed in people with food intolerances or allergies. In contrast, the body's own cells, which have been transformed into cancer cells and multiply in an uncontrolled manner, are a major hazard that the immune system must not overlook. Differentiating between what is dangerous and what is harmless is a difficult task for the immune system. How it solves them is not yet fully understood in detail.

Natural killer cells are very old in evolutionary terms and are part of the innate immune system. They are one of the first lines of defense in the fight against infection and cancer. For example, they form important messenger substances and can kill degenerate and infected cells. But how can NK cells in our body recognize cells that are infected with viruses or that have become cancer cells? They do this using what was known as the "missing self" nearly twenty years ago. NK cells have so-called receptors on their cell surface, which conduct signals from the environment into the interior of the cell. Some of these receptors recognize a structure that is present on almost all cells in our body and that is known as "MHC class I". When the receptors of the NK cells detect the presence of MHC class I on the surface of other cells, they send a negative signal inside the NK cell. In this way, the NK cells are immobilized: the body's own cells are protected from being destroyed by NK cells.

Some viruses are able to suppress MHC class I in infected cells: they thereby escape the surveillance of that part of the immune system that needs MHC class I for its work. However, NK cells no longer receive a negative signal when they encounter virus-infected cells without MHC class I. The absence of the signal shows the NK cell that something is wrong with this cell. The NK cell uses MHC class I as a kind of molecular ID with which it checks the identity and integrity of cells in our body. If the ID card is present, the NK cell is switched off by receptors that send a negative signal into the cells. If this ID is missing, for example on virus-infected cells or cancer cells, the NK cell becomes active. In this way, the NK cell is able to differentiate between "good" - with ID - and "bad" - without ID.

The activation of NK cells is also mediated by receptors on their surface. These receptors send a positive signal into the NK cell. In its decision-making process, the NK cell must weigh up negative and positive signals. It is precisely this interplay between positive and negative signals at the molecular level that is the subject of research in our laboratory.

We have already discovered that the receptors that switch on NK cells depend on certain areas in the cell membrane. These areas, known by experts as "lipid rafts", can be imagined as small islands in the shell of cells on which there are structures that need activating receptors for their work. Therefore, the receptors have to be in the lipid rafts if they want to turn on NK cells. Those receptors that silence the NK cells through a negative signal prevent the activating receptors from moving into the lipid rafts. We suspect that these special membrane areas are the switching point for the regulation of NK cells through positive and negative signals.

For this reason, our future work will deal with how lipid rafts work. We want to understand why activating receptors are located in these special membrane areas and which structures within the lipid raft are important for switching on the NK cells. Furthermore, we want to clarify what the molecular mechanism is by which the negative receptors prevent the presence of activating receptors in the lipid rafts in order to immobilize the NK cells. Only when you understand the basics of switching NK cells on and off can you develop strategies to influence NK cell activity. By weakening the influence of negative receptors or strengthening the signals of the activating receptors in the lipid rafts, one could support the NK cells in their fight against cancer cells or infected cells.

Dr. Carsten Watzl
Institute for Immunology
Im Neuenheimer Feld 305, 69120 Heidelberg
Telephone (0 62 21) 56 45 88
E-mail: [email protected]

Carsten Watzl is the winner of the BioFuture young talent competition (Federal Ministry of Education and Research 2004).