Epithelial chemokine CCL25 integrates T cell development and intestinal homeostasis.

The chemokine receptor CCR9 regulates thymus colonization by T progenitors and intestinal accumulation of TCRγδ+ intraepithelial lymphocytes (IELs). CCR9-ligand chemokine CCL25 is expressed predominantly in the thymus and the small intestine. By engineering tissue-specific CCL25-deficient mice, we demonstrate that CCL25 locally produced by thymic and intestinal epithelial cells individually supports developing T cell localization in the thymus and TCRγδ+ IEL accumulation in the small intestine, respectively. Our results also reveal that thymic epithelial CCL25 facilitates T cell positive selection in the thymic cortex. We further find that intestinal epithelial CCL25 promotes nutrient sensing in the small intestine. These results indicate that epithelial CCL25 directs thymic T cell development and intestinal homeostasis in a tissue-specific paracrine manner.