T-cells in boot camp
The T-cells of the immune system have a critical function in combating viruses and bacteria. But they only respond to foreign protein snippets that are presented to them on the surface of other immune cells. What is important here is that they attack none of the body’s own structures. As a team of LMU immunologists led by Professor Ludger Klein has now demonstrated in a mouse model, a mechanism known from a different context is borrowed for the T-cells’ corresponding training: autophagy is a mechanism in which cell components are broken down and recycled, in order to provide the body with energy, for example. The new work points to this mechanism being used for other purposes in the thymus gland, a kind of “school for T-cells”, in order to make the broken cell pieces visible to adolescent T-cells. The T-cells are presented with an immunological image of all proteins of the organism. T-cells that respond to these structures are destroyed before they reach the blood circulation – and an attack on the body’s own proteins is thus prevented. “The immune system of mice in which autophagy in the thymus is directly inhibited is utterly derailed,” says Klein. The T-cells of the animals wandered into certain organs and attacked them. Severe intestinal inflammations and damage to the liver, lungs, skin and uterus were the consequences. “Autoimmune diseases like these also occur in people,” explains Klein. “We can now formulate new working hypotheses on how these diseases arise.” (Nature, 13/8/2008)
Old and misfolded proteins are recycled by a process known as autophagy (“self-eating”). In the case of nutrient deficiency, this process is switched on in order to hack up cell structures and thereby deliver the body with fuels for producing energy. Otherwise – the predominant belief is – the body's cells only very rarely find themselves in the predicament where they have to break down their own components. According to the results of the present study, however, autophagy fulfils yet another important and extraordinary function: It protects us against our own immune system. As the team around Klein has demonstrated, the epithelial cells of the thymus gland exploit this mechanism in order to present all of the body’s proteins in pieces to adolescent T-cells. That way, T-cells that do not respond to viruses and bacteria, but to the body’s own structures instead, can be sentenced to cell death.
This test was performed in an animal model. Yet, there is already the first evidence that the same mechanisms might be effective in humans as well. It was shown in two recent independent studies, for example, that there exists a genetic connection between a component of autophagy and the inflammatory gastrointestinal affliction Crohn’s disease – an autoimmune disease. The molecular connection, however, has not yet been explained. The starting point of the study organized under Klein’s direction, which already started at the Institute for Molecular Pathology in Vienna, was provided by results from a cooperative partner, Professor Noboru Mizushima, from Tokyo Medical and Dental University. He had shown that the epithelial cells of the thymus were the only tissue type of the body in which an elevated rate of autophagy was detectable, even without hunger – i.e. without an increased need for energy.
“We have already known for nearly ten years that these cells in particular are important for defusing T-cells that want to attack the body’s own structure,” reports Klein. “Back then, we discovered, along with colleagues in Heidelberg, that the thymic epithelial cells are capable of producing practically every protein of the body by a mechanism that is still a mystery. But it was unclear how they were able to present the important protein snippets – called epitopes – on their surface in order to train T-cells.” This is because T-cells do not react to free-floating foreign bodies in the body fluids, rather they only recognize protein fragments embedded into so-called MHC II molecules, using their T-cell receptor.
“Astoundingly, practically every single one of our millions of T-cells in the thymus gets a different T-cell receptor due to a principle of randomness, so that the immune system is able to recognize just about every type of pathogen,” explains Klein. “And yet, receptors that would respond to the body’s own protein fragments also get created this way.” These must not be allowed to leave the thymus, otherwise autoimmune diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis can develop. They must be tested early on, sorted out and rendered harmless. The thymic epithelial cells are responsible for this. In every T-cell activated by them, apoptosis – programmed cell death – must be triggered.
According to prevailing doctrine, however, a thymic epithelial cell ought not to be able to fulfill this function at all. Namely, it ought not to present any protein segments it has created itself embedded in its MHC II molecules – in the cells of the immune system, this place is normally reserved for foreign antigens. In order to channel the body’s own protein snippets to this position, the epithelial cells of the thymus require misused autophagy, the researchers around Klein believe. The process probably allows the epithelial cells to hack up the body’s own proteins, and to present them ultimately to the T-cells. At least, that is what the results now published suggest.
In the decisive experiment, the researchers specifically switched off the mechanism of autophagy in the thymic epithelial cells. “After five weeks, we could see with our bare eyes that the modified mice were not doing well,” says Jelena Jedjic, a co-author of the study. “The skin of the animals was scaly, and they had massively lost weight.” Immunological analysis of the organs revealed drastic effects of the genetic modifications: T-cells had departed from the blood and lymph and wandered into organs, where they had caused tissue damage.
“However, we don't know why they only attacked certain organs,” states Klein. “But it was still very interesting that the intestinal system in particular was so heavily damaged, because this disease pattern is very much reminiscent of the human autoimmune disease Crohn's disease. We now intend to clarify how autoresponsive T-cells can escape selection in the thymus, and what effects faulty autophagy in the thymus can have. After all, this should lead us to a better understanding of the autoimmune diseases, and perhaps even to therapies.”
“Autophagy in thymic epithelium shapes T-cell repertoire and is essential for tolerance”
Ludger Klein et al.
Nature, Advance Online Publication, DOI: 10.1038/nature07208
Professor Dr. Ludger Klein
Institute for Immunology
Tel.: +49-89-2180 75696
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