Worldwide, a steady increase in allergic diseases can be observed within the last decades. This rapid increase cannot be explained by genetic reasons as much more time would be required when considering time span of human generations. Thus, alterations of our environment induced by changes in life style conditions, mode of birth, food intake, use of medication such as antibiotics, etc. is likely a contributing factor to the recent rise in allergic diseases. Interestingly, most of the currently discussed changes in life style factors affect directly or indirectly the composition of our microbiome (including bacteria, fungi and viruses). Our microbiome virtually colonizes all our body surfaces and is part of any healthy individual. Currently it is believed that alterations of this microbiome is one of the most likeliest factors leading to a raise in allergic diseases. This concept is supported by epidemiological studies demonstrating that growing up in a rural area or farm environment associated with traditional farming (in contrast to industrial farming) is indeed a major protective factor to prevent e.g. allergic asthma. Thus, the microbiome is very likely one of the key determinants affecting susceptibility to allergic diseases but underlying mechanisms remain poorly understood.
In this project, we hypothesize that alterations in the immune system due to differences in microbial compositions is a common and underlying cause for the above described observations. In particular, the immune system of the gastrointestinal tract where microbial burden is highest and were a big surface area allows for various interactions between the host and its microbial symbionts is of particular importance. Based on our previous results based on in vivo animal models we hypothesize that a specialized population of regulatory T cells (so-called type 3 Tregs) co-expressing the transcription factors Foxp3 and RORgt is a central player in this process for the following reasons: a) Type 3 Tregs develop after weaning and reside within the intestinal tract b) Type 3 Tregs have the highest frequencies where microbial exposure is highest (colon>small intestine>secondary lymphoid tissues associated to the intestinal tract>spleen/distal lymph nodes>thymus) c) Type 3 Tregs are absent in germfree or broad spectrum antibiotic-treated animals and d) genetic ablation of Type 3 Tregs leads to exaggerated type 2 immune responses also found in germfree conditions. Assessing the microbial habitat within the intestinal tract is still a very difficult task because interindividual variety is high and complex interdependent interactions between hundreds of microbial species cannot be easily studied in vitro because many of these species are not yet cultivable. Therefore, type 3 Tregs may serve as a faithful readout for inefficient induction of intestinal homeostasis which can affect both local and systemic diseases associated to a loss of immunological tolerance.
In this project we aim to identify thus both microbial and host-intrinsic pathways that positively or negatively regulate the induction and maintenance of type 3 Tregs. We anticipate that this knowledge can serve as a useful tool to diagnose and in the future possibly also prevent allergic and other diseases associated to a loss of immunological tolerance to foreign antigens.
