Discrete Intestinal Stromal Cell Populations Differentially Express the Atypical Chemokine Receptor, ACKR4

Intestinal immune responses are dependent on the action of chemokines and their receptors. CCL19 and CCL21 drive the CCR7-dependent migration of dendritic cells from the lamina propria (LP) to the mesenteric lymph nodes (MLN), whilst CCL25 recruits CCR9⁺ gut-homing leukocytes from the circulation to the LP of the small intestine. CCL19, CCL21 and CCL25 also bind to the atypical chemokine receptor ACKR4 (CCRL1). Interestingly, rather than inducing cell migration, ACKR4 binds and internalises its ligands, targeting them for intracellular degradation. ACKR4 is expressed by lymphatic endothelial cells in secondary lymphoid organs, including the MLN. However, if and where it is expressed in the mucosa is unknown. Using ACKR4-eGFP reporter mice, we show that ACKR4 expression in the intestinal LP is restricted to a discrete population of fibroblasts. This ACKR4-expressing fibroblast population has a unique transcriptional signature, thus differentiating them from other intestinal fibroblasts. To explore the biological and functional significance of ACKR4 expression on intestinal stromal cells, we have compared DC migration from the LP to the draining MLN in WT and ACKR4-deficient mice. These studies aim to establish the role of ACKR4 in intestinal immunity, and dissect the complexity of chemokine networks in the intestine.