Type 2 immune responses promote tissue homeostasis as well as tissue remodeling and protect against infections with macroparasites but can become detrimental when triggered against non-infectious environmental stimuli1. The cytokines IL-25, IL-33, and TSLP are strong activators of type 2 inflammation in tissues via stimulation of group 2 innate lymphoid cells (ILC2s) and other innate immune cells, such as eosinophils, mast cells, basophils, and alternatively activated macrophages resulting in a cytokine milieu, which promotes differentiation of T helper 2 cells and secretion of immunoglobulin E.1,2 Although ILC2s become quickly activated, the precise role in orchestrating type 2 immune responses remains elusive due to the limitations in specifically targeting this population in the presence of adaptive immune cells because of the large overlap in expression of ILC2s with T cells and other immune cells.
To guide over this major limitation in the field we could recently generate and evaluate a model to specifically deplete ILC2s. Exploiting the possibilities of this newly generated tool, this proposal now aims to systematically investigate immunoregulation mediated by ILC2s at mucosal surfaces of the gastrointestinal tract. Using a combination of immunophenotyping, state-of-the-art sequencing technology, and microbiome analysis we will explore how the adaptive immune response, such as affinity maturation of immunoglobulins is affected in the absence of ILC2s.3,4 The signal circuits involving ILC2-mediated regulation of microbiota either directly or indirectly via regulation of immunoglobulins and B cell responses will be investigated as well. Our working hypothesis predicts that ILC2s determine the microbiota colonization in early life through different pathways including but not limited to affinity maturation of antibodies. The models to test this hypothesis are available in our lab and the techniques are carried out on a daily basis without the requirement to establish novel methods from scratch.
Delineating the regulation of type 2 immune responses by ILC2s will be key to understand how type 2 immune responses are orchestrated. Using both focused and global experimental approaches our research has the potential to discover novel molecular pathways, which can be harnessed for the maintenance of homeostasis and prevention of chronic inflammation.