Licensed B cells induce immunotolerance

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