Laboratories in Würzburg, Berlin and Mainz are investigating the genetic regulation of specialized T cells
12.06.2008
T cells play a very important role as part of the immune system. The various types of T cells have different tasks within the immune response. If this defense system fails, conditions such as allergies and autoimmune diseases can develop. The German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) has now approved a research application submitted by laboratories in Würzburg, Berlin and Mainz, the purpose of which is to investigate how genetic control determines the development and function of the various T cells. "We want to find out how the individual T cells function and how their genetic regulation can be directly influenced, so that new therapy methods can ultimately be developed," explains Professor Edgar Schmitt of the Institute of Immunology at the Johannes Gutenberg University in Mainz. The DFG will be initiating the new DFG Transregional Collaborative Research Center (TR 52) Transcriptional Programming of Individual T Cell Subsets on 1 July 2008 and will also be making available about €12 million over the next four years.
T cells are white blood cells formed in the bone marrow that mature in the thymus. They can recognise invading exogenous organisms and substances and then provide a defensive response in many forms, while at the same time a specialized T cell population actively prevents any auto-aggressive immune reaction against the body's own cells. These so-called physiological regulatory T cells have been extensively studied by Edgar Schmitt's team. "We shall be using the DFG Transregional Collaborative Research Center to investigate how a specialized T cell develops and how it functions. In Mainz, we will be taking a closer look at the regulatory T cells, but all subpopulations of T cells will be investigated jointly with the other sites," says Schmitt. The focus is on the exact way in which the genetic information is regulated to enable these cells to systematically to carry out their functions. If this can be established, it would be possible, for example, to switch off auto-aggressive T cells, and to influence other regulatory cells in such a way that autoimmune diseases could be prevented. "Based on our initial data, we have already been able to outline therapeutic approaches that will have a targeted effect on asthmatic diseases," explains Schmitt.
Investigations conducted by his team have shown that cyclical adenosine monophosphate (cAMP) is essential to the suppressive properties of physiological regulatory T cells. These cells have high concentrations of cAMP, and they transmit it to target cells via channels - the so-called 'gap junctions'. "As a result, these target cells are extensively inhibited and can therefore not act as central drivers of an auto-aggressive or allergic immune response such as asthma." Schmitt and his colleagues have discovered that the so-called phosphodiesterases (PDEs) antagonize this suppression. These enzymes break down cAMP and therefore counteract inhibition by the regulatory T cells. "We were thus able to achieve a significant alleviation of asthma by systematically inhibiting these PDEs in the mouse model."
The scientists involved hope that the increase and concentration of scientific research in Germany concerning the transcriptional control of the genetic expression of T lymphocytes will contribute towards the discovery of the central trigger points of the immune reaction. The most important factors in the transcriptional control of T cells are to be identified and their function is to be decoded in in vivo mouse models, while methods of achieving targeted modulation of the transcription process are also to be researched. The institutions in Würzburg, Mainz and Berlin, with their varied expertise, will concentrate here on the cellular and molecular biological aspects of T cell biology. Several institutions and researchers in Mainz are involved in this project: Dr. Sabine Ohlemacher and HD Dr. Helmut Jonuleit (dermatology), PD Dr. Kerstin Steinbrink (dermatology), Professor Susetta Finotto (1st Medical Clinic), Professor Ari Waisman (1st Medical Clinic), HD Dr. Kurt Reifenberg (Central Laboratory Animal Facility - CLAF), Dr. Jürgen Siebler and Professor Markus Neurath (1st Medical Clinic), as well as Dr. Tobias Bopp and Professor Edgar Schmitt (Institute for Immunology).