Heterogeneity of the intestinal mononuclear phagocyte compartment in health and inflammatory bowel disease

Understanding of mononuclear phagocyte (MNP) diversity in the human intestine and the alterations this compartment undergoes in inflammation remains incomplete. Here, we used single-cell RNA sequencing, cellular indexing of trancriptomes and epitopes by sequencing, flow cytometry, and imaging to explore MNP heterogeneity in human ileal and colonic laminae propriae (LPs) in health and Crohn's disease (CD). In addition to monocytes, macrophage subsets, and conventional type 1 dendritic cells (cDC1s) and cDC2s, we found a CD1c⁺ cDC subset with transcriptional features of DC3s. Using computational tools, we identified monocyte-to-macrophage trajectories as well as putative subset-specific DC precursors. We further showed that LP CCR7⁺ cDCs are increased in CD and provided evidence that these cells arise from intestinal cDC2s/DC3s but not cDC1s. Collectively, these findings extend our current understanding of intestinal MNP diversity and development, highlighting both tissue-specific and inflammation-induced changes in MNP composition and function.