Intestinal Treg-M cell regulatory circuit in health and disease

 
Major challenges in studying inflammatory disorders include establishing causality—distinguishing cellular and molecular changes in immune cells that drive disease from those that arise as secondary consequences of inflammatory tissue damage—and shifting from a focus on individual cell types toward understanding how groups of cells function as circuits within inflamed tissues. These challenges are particularly acute in IBD where it remains unclear whether breakdowns in the intestinal barrier initiate or result from inflammatory immune activation. Our proposed studies focus on an understudied intestinal epithelial cell lineage, microfold (M) cells, which sample and deliver luminal antigens to immune cells in the underlying tissue and act, therefore, as a key cell type in balancing barrier integrity and immune activation. We propose that M cells function as a component of a spatially organized cell circuit with regulatory T cells and antigen-presenting cells in the inductive subepithelial dome niche of Peyer’s patches. We will dissect the organization and function of this circuit using novel genetic tools and integrated multi-prong cutting-edge analyses in mouse IBD models, intestinal infection and homeostatic conditions. These studies will provide biological and mechanistic frameworks for a novel immune-epithelial cell circuit whose malfunction may contribute to intestinal inflammatory disorders.