Microbiota-immune cell interactions play a vital role in defenses against potentially harmful external organisms such as viruses and bacteria, and environmental agents including food. Microfold (M) cells are specialized cells within the epithelium of the intestines that sample the gut contents and pass them to the local guardians – a complex array of immune cells. Once harmful invaders are detected by the immune cells, they swing into action to fight the infection. M cells provide the pivotal link between the gut lumen and the immune cell network, positioned to rapidly orchestrate appropriate immune responses. Exactly how M cells orchestrate these events, however, is not clear.
Despite their critical function, to date few specific tools exist to study intestinal M cells, the molecular mechanisms that regulate their generation, or how they drive mucosal immunity. To overcome this gap, we have generated novel gene modified mouse strains to allow us to visualize M cells and tease apart their behavior. We discovered that M cells are present along the entire intestinal tract, and not just localized to the Peyer’s Patch as previously thought. Analysis of gut epithelial cells at different sites along the gut using single cell RNA sequencing revealed tissue-specific heterogeneity allowing us to define distinct gene signatures for M cells based on their location. These molecular blueprints identify distinct maturation programs that reflect local environmental cues shaped by the ingested material and the microbiota. Collectively, these features shape the delicate network of immune cells and show how the body can regulate gut region-specific disease. Future experiments will explore these pathways and their impact on gut homeostasis.