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Two separate defence systems?

Are the innate and the adaptive immune systems really completely independent from each other? Dr. Mathias Lucas from the University of Freiburg investigates receptor proteins that are found in the cells of both systems. It is possible that such systems might not only play a role in infections or cancer, but also in autoimmune diseases such as rheumatoid arthritis.

The innate immune system is found in almost all groups of organisms. In mammals, the innate immune system comprises, for example, the natural killer cells that carry specific markers on their surface. These surface markers recognise body cells that have been infected by viruses or bacteria or that have turned into cancer cells and that reveal these changes by presenting specific signalling molecules on their surface. This mechanism works from the day a mammal is born and absolutely no training is needed. The cells of the adaptive immune system have to learn distinguish between the body's own cells (self) and unwanted invaders (non-self). The recognition molecules on the surface of these cells only react to very specific motives. These motives might also originate from the body’s own healthy tissue. However, a negative selection process enables the body to remove such autosensitive cells very quickly, leaving behind immune cells that sound an alarm upon the intrusion of invaders. Once an organism comes into contact with bacteria or viruses, then an appropriate immune cell subpopulation that carries suitable recognition structures proliferates. Some of these cells become memory cells that are able to recognise a previously encountered antigen when exposed to it for a second time, making them thus able to produce a stronger and faster immune response. The body has learnt to respond to this particular intruder.

Interaction on the molecular level

T-lymphocyte under the electron microscope. © Dr. Triche, National Cancer Institute

"Text books have for a long time taught us that the cells of the innate and adaptive immune systems carry completely different types of receptors for the recognition of foreign or defective structures," said Dr. Mathias Lucas from the Institute of Medical Microbiology and Hygiene at the Freiburg University Medical Centre. "But over the last few years it has become clear that T-cells have receptors that are typical for natural killer cells, which are actually part of the innate immune system." T-cells are white blood cells (leukocytes) that are part of the adaptive immune system. They normally recognise foreign substances that are presented to them by the macrophages. This triggers the release of cytokines, thereby inducing a comprehensive immune response.

The two defence systems seem to overlap at this point. Lucas and his team have found T-cells of a specific subtype (CD4) with the aforementioned receptors in mice that were infected with bacteria or viruses. One of these receptors, the NKG2D receptor, which is normally found on natural killer cells, recognises signalling molecules on cell surfaces that suggest that the bearer is infected. The receptor then activates the natural killer cells. Another receptor, Ly49, inhibits the natural killer cells. Why do the cells of the adaptive immune system carry such receptors?

NKG2D receptors with their DAP10 molecules that protrude into the cell interior are located on the surface of natural killer cells (brown line). They control a complex network of signalling pathways in the interior of the cell, including processes such as the proliferation or release of cytokines. T-cell receptors (in brackets) are also found on the surface of T-cells; the NKG2D receptors do then not activate signalling pathways but only support the T-cell receptors. © Dr. Mathias Lucas

Lucas and his team hope to answer this question using transgenic mouse strains. They know from the experiments of other researchers that receptors such as NKG2D on T-cells do not trigger a reaction on their own. This is not the case in natural killer cells. The receptors on T-cells support only T-cell receptors (TCRs) that confer T-cells their specificity for certain foreign (non-self) structures. In a transgenic mouse model, Lucas and his team have tested whether the NKG2D receptors play a role at all. They infected healthy mice with genetically manipulated T-cells in which a helper molecule for the NKG2D receptor, DAP10, was either switched on or off. DAP10 is necessary for the NKG2D to be able to transfer a message into the cell. If DAP10 was fully functional, then the mice developed memory cells in their lungs within a few weeks. If DAP10 was switched off, the researchers found no memory cells.

The problem of “self” and “non-self”

“We assume that the NKG2D receptor enhances the immune response and promotes the formation of memory cells,” said Lucas. “It is also possible that it makes the memory cells more sensitive to previously encountered bacteria.” In order to test whether cells with NKG2D receptors are more sensitive, Lucas and his team are planning to bring T-cells into contact with small quantities of bacteria. Upon exposure to very small numbers of bacteria, cells with certain T-cell receptors hardly react. Does a cell react if it also has NKG2D receptors on its surface?

Future experiments undertaken at the Institute of Medical Microbiology and Hygiene will show whether this is indeed the case. Lucas has just submitted a proposal to the DFG applying for funds for the project. He hopes that it will not only help them to find how the innate and the adaptive immune system interact whilst defending themselves against intruders. The NKG2D receptors also react to the body’s own signalling molecules, they recognise the “self” of the body. Understanding their function might lead to better insights into autoimmune diseases and Lucas and his team therefore plan to breed mice suffering from rheumatoid arthritis. “Which immune cells proliferate very strongly in such mice?” asks Lucas. “Which cell types carry NKG2D and other receptors of the innate immune system on their surface?” He hopes that he will be able to come up with the first answers in about a year’s time.

Further information:

Dr. Mathias Lucas
Institute of Medical Microbiology and Hygiene
Freiburg University Medical Centre
Hermann-Herder-Str. 11
Tel.: +49 (0)761/203-6546 (Labor –5361)
Fax: +49 (0)761/203 6651
E-mail: mathias.luca(at)uniklinik-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/two-separate-defence-systems