Role of regulatory fibroblasts in eliciting immune tolerance to colitis.

Ulcerative colitis (UC) is characterized by non-resolving pathological inflammation leading to erosion of the colon tissue. Recent studies analyzing gene expression signatures in UC patients highlighted specific colonic fibroblast populations that may contribute to inflammation and disease progression. While these studies emphasize the proinflammatory function of activated intestinal fibroblasts, it is unknown whether subsets of intestinal fibroblasts may fulfill protective regulatory functions required to limit intestinal inflammation. Our studies leverage a novel spatial transcriptomics method (MERFISH) to generate a detailed cellular and molecular atlas of the colon, with an emphasis on elucidating the function of fibroblasts in mouse and human colitis. We discovered a new population of regulatory fibroblasts (Fregs) that differentiate during colitis and suppress intestinal inflammation. In particular, we found that Fregs appear in non-inflammatory regions and promote the differentiation of regulatory B cells (Bregs) and tolerogenic dendritic cells (tolDCs). The goal of this project is to define the molecular framework governing Freg, Breg and tolDC interactions during colitis, and establish the nature of these interactions in human UC. These studies will demonstrate how Fregs orchestrate immune tolerance to colitis and whether failure of this mechanism may contribute to tolerance breakdown in UC.