Identification and Characterization of a Novel RORγt+ DC Subset with Implications for Intestinal Immune Homeostasis 4694

Abstract Description Disruption of immune tolerance leads to a broad range of enteropathies, food allergies and IBDs, which disrupt normal functions of the intestinal mucosa, impair absorption of nutrients and cause systemic leakage of bacterial products. We recently identified a rare subset of RORγt+ cells distinct from ILC3s that exhibit dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, termed RORγt+ DCs, display DC morphology, express MHC class II machinery, and are distinct from known DC and ILC3 subsets. However, they share transcriptional and epigenetic similarities with DC2 and ILC3. RORγt+ DCs proliferate in vitro, differentiate into DC2-like cells, and stimulate allogeneic T cell proliferation. Further investigation revealed an enhancer element accessible in both ILC3 and RORγt+ DC. Knockout of this enhancer resulted in a significant reduction of both cell types and a marked decrease in peripheral Tregs within the intestinal lamina propria and draining mesenteric lymph nodes. Consequently, these mice exhibited increased susceptibility to microbial and food challenges, highlighting the importance of this novel RORγt+ DC subset in maintaining intestinal immune homeostasis. Funding Sources This study was supported by NIH 1R01DK126969; NIH R01DK132327; NIH R01DK30292; T32DK077653 Topic Categories Mucosal and Regional Immunology (MUC)