The role of the intestinal lamina propria stromal compartment in shaping “tissue niches” for oral tolerance and type 2 immunity

• Applicant: Maria Szente-Pasztoi, Ph.D.
• Subject Area: Immunology ; Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458325417

The immune system at the intestinal mucosa faces a unique challenge to discriminate between dangerous pathogens, harmless commensal microbes and dietary antigens. The maintenance of this delicate balance relies on the dynamic adaptation of peripherally induced Foxp3+ regulatory T cells (Tregs). These cells are highly abundant in the intestinal lamina propria (LP) and are able to regulate type 2 immunity. The cellular nature of this ‘tissue niche’ in the intestinal tract remains largely undefined but is certainly guaranteed by local non-migrating cells such as epithelial and stromal cells. We and others have shown that stromal cells in gut-draining mesenteric lymph nodes (mLN) possess tolerogenic properties and promote peripheral Treg induction. However, physiological and immunomodulatory functions of stromal cells within the intestinal LP remain obscure. Even so, it is tempting to speculate that intestinal LP stromal cells are an integral part of the intestinal tissue niche. Therefore, the overall aim of the proposal is to reveal the contribution of LP stromal cells to inflammatory stimuli of type 2 immunity and the maintenance of intestinal tolerance. Our preliminary in vitro data show that LP fibroblastic stromal cells (FSCs) are responsive to environmental inflammatory cues including the hallmark cytokines IFN-γ, IL-17 and IL-4. However, the transcriptional signature and response of LP FSCs during steady state and ongoing type 2 inflammation remain currently unclear. We thus aim to study the in vitro polarization-specific transcriptional signature of LP FSCs and their in vivo modulation in mouse models of type 2 inflammation, such as food allergy and parasite infections. Previous work of us and others demonstrated the crosstalk between LN stromal cells and various immune cells. Therefore, our goal is to investigate the mutual interaction between tissue resident LP FSCs and epithelial cells by establishment of organoid-stromal cell co-culture systems and assess how exposure to type 2 inflammatory signals impact on organoid formation and the ‘tissue niche’-defining nature of LP FSCs. Since postnatal immunity is known for its type 2 biased nature and the lack of microbial exposure, we monitored the postnatal development of intestinal stromal cells, and found that LP stromal cells undergo drastic changes during this period. To understand which programs drive LP stromal cell development, we aim to identify developmental trajectories of LP stromal cells by scRNA-seq. Moreover, we will determine the role of the microbiota-derived metabolite sensing aryl hydrocarbon receptor (AhR) in postnatal development and responsiveness of LP FSCs to inflammatory insults.Gaining insight into the molecular mechanisms whereby LP stromal cells contribute to tolerance and intestinal type 2 immunity anticipates therapeutic roadmaps for the treatment of type 2 gastrointestinal disorders and solid resource for comparison to intestinal cancer-associated FSCs.

• DFG Programme: Research Grants
• International Connection: Brazil, Switzerland
• Cooperation Partners: Professor Dr. Christian Hoffmann; Dr. Jörn Pezoldt