02:51pm Wednesday 20 September 2017

Licensed B cells induce immunotolerance

Scientists at the Ludwig-Maximilian-University (LMU) in Munich and the German Cancer Research Center have now discovered that B cells migrating into the thymus also contribute to immunotolerance. On entering the thymus, they alter their molecular makeup and become “licensed” to induce tolerance.

enlarged view © Sheena Pinto,DKFZ

The body’s own immune system can easily become a threat: When immune cells turn against the body’s own tissues, they provoke autoimmune diseases that may even end in death. The body has therefore built up solid defenses against such lapses. The immune system’s T cells are carefully regulated for this purpose. This takes place in the thymus, a small, gland-like organ behind the sternum. This is where the T cell precursors that recognize endogenous proteins by means of their antenna-like receptors are immediately selected out. Immunologists call this process “negative selection”, and the result is “central tolerance”.

Bruno Kyewski, an immunologist from the German Cancer Research Center, is an expert in T cell tolerance. Some years ago, he elucidated processes in the thymus that are instrumental in the selection of autoreactive T cells. But there’s a trick involved: whereas all the body’s other cells produce only those proteins that are needed in a particular tissue, thymus cells (medullary thymic epithelial cells) may produce an extremely broad spectrum of proteins. They act as a kind of “showroom” for all endogenous proteins.

A T cell precursor maturing in the thymus whose receptor happens to fit one of these displayed proteins is eliminated immediately. The regulator protein Aire plays a key role in this process. It is this transcription factor that enables the thymus cells to produce their full arsenal of endogenous proteins.

Together with Ludger Klein and his colleagues from LMU Munich, Bruno Kyewski has now discovered that B cells migrating into the thymus also express Aire and are thus theoretically able to induce tolerance. B cells are the immune system’s second major arsenal. The teams from Munich and Heidelberg discovered that the B cells in the thymus change their molecular makeup at the same time as they express Aire and receive a “tolerance license”, as it were.

The scientists asked themselves whether these tolerance-licensed B cells can actually contribute to the elimination of autoreactive T cells. Their approach was to inject the gene for the viral protein hemagglutinin under regulation by the transcription factor Aire into the B cells of mice. If the animals’ B cells received their “tolerance license” in the thymus, the T cell precursors directed against hemagglutinin were indeed eliminated.

“Reliable immunotolerance is important for an entire lifetime. The body has to ensure that all self-antigens are protected against T cell attacks,” explains Bruno Kyewski. The reason why B cells have to play an important role is that their repertoire of self-antigens in the lymph nodes can change in the course of an inflammatory immune response. These newly created self-antigens could trigger an autoimmune reaction. The researchers speculate that B cells contribute to inducing tolerance in order to protect themselves against T cell attacks on the newly created self-antigens.

Tomoyoshi Yamano, Jelena Nedjic, Maria Hinterberger, Madlen Steinert, Sandra Koser, Sheena Pinto, Norbert Gerdes, Esther Lutgens, Naozumi Ishimaru, Meinrad Busslinger, Benedikt Brors, Bruno Kyewski, and Ludger Klein: Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction. Immunity 2015, DOI: 10.1016/j.immuni.2015.05.013

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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