Interleukin 7 receptor (IL7R) is required for myeloid cell homeostasis and reconstitution by hematopoietic stem cells

Cool, Taylor; Worthington, Atesh; Poscablo, Donna; Hussaini, Adeel; Forsberg, E. Camilla

Respiratory diseases are a leading cause of death worldwide, with highly varied vulnerability to disease between individuals. The underlying reasons of disease susceptibility are unknown, but often include a variable immune response in lungs. Recently, we identified a surprising novel role of the interleukin 7 receptor (IL7R), a primarily lymphoid-associated regulator, in fetal-specified, lung-resident macrophage development. Here, we report that traditional, hematopoietic stem cell-derived myeloid cells in the adult lung, peripheral blood, and bone marrow also depend on IL7R expression. Using single and double germline knockout models, we found that eosinophil numbers were reduced upon deletion of IL7Rα. We then employed two Cre recombinase models in lineage tracing experiments to test whether these cells developed through an IL7Rα+ pathway. Despite the impact of IL7Rα deletion, IL7R-Cre labeled only a minimal fraction of eosinophils. We therefore examined the intrinsic versus extrinsic requirement for IL7R in the production of eosinophils using reciprocal hematopoietic stem cell transplantation assays. These assays revealed that extrinsic, but not eosinophil-intrinsic, IL7R is required for eosinophil reconstitution by HSCs in the adult lung. To determine which external factors may be influencing eosinophil development and survival, we performed a cytokine array analysis between wild-type and IL7Rα-deficient mice and found several differentially regulated proteins. These findings expand upon our previous publication that IL7R is required not only for proper lymphoid cell development and homeostasis, but also for myeloid cell homeostasis in tissues. Highlights Loss of IL7Rα resulted in significantly fewer eosinophils in adult mice IL7R-Cre lineage tracing revealed minimal labeling of eosinophils IL7Rα-deficient HSCs robustly reconstituted eosinophils in a WT host WT HSCs failed to fully reconstitute eosinophils in IL7Rα-/- hosts Several cytokines are differentially expressed in WT and IL7Rα-deficient mice