IL7R regulates fetal tissue resident macrophage development

Tissue-resident macrophages (TRMs) play critical roles in tissue homeostasis and disease. Many populations of TRMs derive from fetal progenitors and independently self-maintain across the lifespan through in situ proliferation. Here, we have identified the interleukin-7 receptor (IL7R) as a novel regulator of TRM development. Using an IL7R-Cre lineage tracing model, we observed that adult TRMs in the brain, epidermis, liver, and lung were highly labeled by IL7R-cre, in the absence of IL7Ra mRNA or protein expression. To gain insight into developmental expression of IL7Ra, we profiled surface expression, mRNA expression, and IL7R-cre driven labeling across fetal development. Erythromyeloid progenitors, putative TRM precursors, were barely labeled by IL7Ra-cre, and IL7R deletion did not affect YS hematopoiesis. In contrast, we observed IL7Ra mRNA expression in fetal monocytes, and robust IL7Ra surface expression on developing TRMs during late gestation. Sorted Ly6chi fetal liver monocytes cultured ex vivo with M-CSF differentiated into macrophages expressing IL7R, suggesting a precursor-product relationship. Blockade of the IL7R with a monoclonal antibody during gestation impaired liver, lung, and epidermal TRM cellularity at birth, with a concomitant increase in cellularity of liver monocytes, suggesting that IL7Ra regulates TRM differentiation from fetal monocytes during fetal development. These data reveal dynamic regulation of IL7Ra expression in TRMs and TRM precursors during late gestation, and provide evidence that IL7R signaling regulates fetal TRM development. Ongoing work addresses downstream signaling and the specific developmental processes regulated by IL7R signaling during fetal TRM development.