Research Focus

How intestinal microbiota and the immune system are regulated and maintain a healthy, symbiotic relationship.

The Geuking lab develops genetically modified microbes and uses state-of-the-art methods that allow for controlled and defined experiments. Specifically, we are looking at how the microbiota modulates T helper cell response –– and how the microbiota is affected when these cell responses are directed at it. These are important parameters for designing therapies where the microbiota is used to therapeutically modulate immune responses in disease.

It has been demonstrated that the intestinal colonization even with a limited microbiota with low diversity requires induction of regulatory T cells (Treg) to establish immune homeostasis. This induction of immune regulation could potentially be therapeutically exploited. In caveat, however, is that the antigen-specificity of the induced Treg remains elusive. Therefore, we developed tools that allow us to address whether a microbiota with regulatory immune capacity also has the capacity to modulate antigen-specific T cell responses towards a regulatory phenotype. This would be essential for the rational design of therapies involving the microbiota to modulate antigen-specific responses involved in disease.

Impact of antigen-specific antimicrobial T helper cell responses on the function and composition of the microbiota.

CD4+ T helper cells come in different flavours called effector functions. Some are more regulatory like Foxp3+ Treg while others are more pro-inflammatory such as interferon- producing T helper type 1 or interleukin-17 producing T helper type 17 cells. Nevertheless, all of these are important in appropriate adaptation and control of the intestinal microbiota. The prime example for this is the presence of dysregulated immune responses against the microbiota in inflammatory bowel disease that contribute to this chronic disorder.

The goal of this research area is to define how T helper cells with different effector functions differentially impact on the microbiota. This is addressed by measuring alterations in the composition of the microbiota and, more importantly, measuring changes in the transcriptional (gene expression) activity of the targeted microbial species.

How does the interaction between intestinal microbiota and the immune system affect health and diseases?

The microbiota has been shown to be implicated in a range of immune-mediated disorders including inflammatory bowel disease, autoimmunity, and allergy. Therefore, altering the composition or function of the microbiota is a promising therapeutic approach to modulate immune responses involved in disease. Because T helper cells are involved in both immune adaptations to colonization and pathologic processes in disease, the lab focuses on the interaction of the microbiota with T helper cells.

The team uses germ free mice in combination with genetically modified commensal species to interrogate whether and how the microbiota can modulate T helper cell responses. This allows for carefully controlled and defined experiments to study how the microbiota modulates T helper cell response, but also how, in return, T helper cell responses directed at the microbiota impact on the microbiota at the level of transcriptional or metabolic activity and microbiota composition.

These are important parameters that need to be defined to be able to rationally design therapies that involve use of the microbiota as a tool to therapeutically modulate immune responses in disease.

This project develops genetically modified microbes as tools to study antigen-specific T helper cell responses in gnotobiotic situations with precisely defined species composition of the microbiota. This allows the use of state-of-the-art technologies including intravital microscopy, next generation transcriptional profiling of individual sorted species, and immunophenotyping using flow and mass cytometry to be used as readouts.