Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions

Project Summary The microbiota provides many key signals that support development and functioning of the immune system. Interactions between host and microbiota allows for proper induction of immune responses against pathogens. These interactions are also necessary to limit inflammatory immune responses against the microbiota which, if left unchecked, will result in inflammatory conditions including inflammatory bowel disease. Many intestinal cell types including immune cells and the intestinal epithelium recognize and respond to the microbiota. It is unclear how such signals are integrated to support homeostasis. In humans as well as in animal models of disease, compositional changes in the microbiota, also known as dysbiosis, correlate with increased susceptibility to inflammatory disease. Understanding the role of individual microbes within the community would allow for the development of novel mechanistic approaches to restore homeostasis in the case of inflammatory disease. We identified a subset of mucosa associated E. coli that induce intestinal macrophage production of IL-1b. This activates innate protection of the intestinal barrier but also drives proinflammatory T cell responses against these E. coli. Specific characteristics of these E. coli as well as how they interact with the host immune system likely drives these responses. In Aim 1 of the proposed work, we will use in vitro and in vivo models to determine how these E. coli activate IL-1b production. In Aim 2 we will define the regulation and consequence of T cell responses against these E. coli. Together, these studies will identify molecular crosstalk between intestinal microbes and immune system that underlie pro-inflammatory responses against the microbiota. Understanding these signals will allow us to identify mechanisms for regulating these pathways and reducing unnecessary intestinal inflammation.