Project Details
Projekt
Characterization of mononuclear phagocyte populations that mediate microbiota-ILC3 interactions
Applicant
Professor Dr. Andreas Diefenbach
Subject Area
Immunology
Term
from 2013 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 237746564
It is becoming clear that the commensal microbiota is important in controlling differentiation and function of immune system components. In addition, it is believed that immune cells can control the composition of microbial communities residing on epithelial surfaces. Much of this complex crosstalk is not well understood. We and others have recently identified novel subsets of innate lymphocytes that are now widely referred to as innate lymphoid cells (ILC). Retinoic acid-related orphan receptor gamma-t-expressing (RORgt+) ILC, a subset of ILC, are potent producers of cytokines such as IL-22 and IL-17 and have been shown to fortify the intestinal epithelial barrier by directly controlling the expression of tissue-protective genes in Paneth cells and stem cells. Our preliminary data demonstrate that differentiation and function of RORgt+ ILC is controlled by the microbiota at various central checkpoints and that deficiency of RORgt+ ILC led to changes in the composition of microbial communities and increased susceptibility to inflammatory bowel diseases. Here, we will experimentally test our overall hypothesis that the intestinal microbiota controls differentiation and function of RORgt+ ILC and that RORgt+ ILC shape the composition of microbial communities. Using gnotobiotic approaches, we will identify specific classes of microbiota that control function and differentiation of RORgt+ ILC. It will also be determined if bacterial communities that increase or repress function of RORgt+ ILC have an impact on the development of intestinal inflammation. It is unknown which cell type(s) sense the presence of microbes as RORgt+ ILC do not express pattern recognition receptors. Our preliminary data show that the myeloid-derived cytokines IL-1 beta and IL-23 are central mediators for differentiation and function of RORgt+ ILC. However, the cellular sources of these cytokines are unknown. Using mice in which various subsets of myeloid cells can be ablated, we will identify the relevant populations controling differentiation and function of RORgt+ ILC. Finally, we will employ metagenomic sequencing analyses of bacterial 16S rRNA sequences to determine if'RORgt+ ILC control the composition of microbial communities residing in the intestine. Collectively, these studies will constitute an unprecedented interrogation of the crosstalk between microbial communities and components of the innate immune system possibly revealing evolutionary ancient circuits that protect the epithelial barrier. Such circuitry may be harnessed for the development of novel therapeutic options of chronic inflammatory disorders.
DFG Programme
Priority Programmes
