On the origin of tissue-resident macrophages

It is increasingly recognised that haematopoietic stem cells (HSCs) are not the only source of adult immune cells in mammals. In particular, many tissue-resident macrophages (trMacs) are known to derive from non-HSC-dependent lineages, with yolk sac-derived erythromyeloid progenitors (EMPs) thought to be the initial cell of origin. However, relatively little is known about the mechanisms regulating the differentiation of trMacs during foetal life. Here, Anna Beaudin, Camilla Forsberg and colleagues show that efficient trMac development is dependent on the interleukin receptor IL7Rα, previously known as a regulator exclusively of the lymphoid lineage in adult haematopoiesis. Using lineage-tracing approaches, they show that adult trMacs in a wide range of tissues derive from IL7Rα-expressing cells. The authors show that IL7Rα is not expressed in the early EMPs, but is specifically upregulated as foetal monocytes begin to differentiate into trMacs in their target tissues. When IL7Rα function is depleted, foetal trMac differentiation is impaired, though maintenance of the population in the adult is unaffected. In addition to identifying an unexpected role for IL7Rα in myeloid differentiation, this work provides further insights into the mechanisms regulating the establishment of trMacs.