We are interested in the establishment, maintenance and break of immunological tolerance in the intestinal system with a particular focus on prevention of allergic diseases. We believe that a better understanding of the multiple interactions between a healthy microbiota with the innate and adaptive immune system is mandatory for this task. The identification of novel mechanisms will contribute to our knowledge on how the intestinal homeostasis is maintained in general and how such mechanisms influence immune responses elsewhere in the body.
Why is intestinal tolerance so important?
In general, the intestinal immune system needs to be tightly controlled as the absence of a tight physical barrier and the presence of a multitude of food- and microbial derived antigens together with a whole variety of so-called MAMPs (microbe-associated molecular patterns) in the gut may facilitate constantly unwanted immune responses against harmless antigens. Furthermore, the microbiota might undergo rapid changes due to changes in food intake (e.g. weaning), use of antibiotics or other lifestyle changes. Tolerance mechanisms need to be in place to deal with these changes, especially with regard to the adaptive immune system. Furthermore, facultative pathogens in the gut are another challenge for the intestinal immune system: Under healthy conditions, tolerance needs to be established against a given antigen from a commensal whereas the same antigen might be found also in a pathogenic situation. One key player for the induction of oral tolerance are the so-called induced regulatory T cells (iTregs). These cells – in contrast to their thymic-derived counterparts - are thought to develop preferentially in the GALT (gut-associated lymphoid tissues) from naive T helper cells under tolerogenic conditions.
We aim to study induction and maintenance or failure of induction of these iTregs as key player in specific oral tolerance in order to prevent diseases or improve patients life that suffer from Ulcerative Colitis, Crohn’s disease or severe food allergy.
The function of ROR(γt)+ T cells
We currently address questions on the differentiation pathways and checkpoints of iTregs and related T helper cell differentiation in the intestinal context by using a series of transgenic mice. We already identified the RAR-related orphan receptor gamma t (ROR(γt)) as a critical transcription factor to prevent the spontaneous development of TH2 and/or TH17 cells in the intestinal lamina propria. Interestingly, ROR(γt) is expressed by a subset of Foxp3+ regulatory T cells that reside mainly in the intestine making them an interesting target for host-microbiom interaction. Genetic ablation of ROR(γt)-expressing cells together with the development of intestinal disease models, e.g. food allergy will help us to understand the precise function of these interesting cells in the intestinal context.
Other mucous surfaces
We also study other mucous surfaces that need to establish tolerance against harmless antigens. In one approach, we aim - together collaboration partners - to better understand tolerance in the lung by identification of allergenic factors of the environment (e.g. pollen). This knowledge is then used for the identification of cellular and molecular mechanisms that have the capability to break tolerance. Finally, we would like to test whether similar mechanisms exist in humans and whether a failure of these newly identified mechanisms contribute to human diseases.
Dr. rer. nat. Caspar Ohnmacht
Zentrum Allergie und Umwelt (ZAUM)
Technische Universität und Helmholtz Zentrum München
Ingolstädter Landstraße 1
Phone: +49 89 3187-2556