Heterogeneity of IL-15-expressing mesenchymal stromal cells controls natural killer cell development and immune cell homeostasis

Bone marrow (BM) mesenchymal stromal cells (MSC) provide microenvironmental niches that support hematopoietic stem cells and regulate hematopoiesis. Whether functional heterogeneity among BM MSCs contributes to the development and survival of distinct immune cell lineages remains incompletely understood. Here, we use an Il15 knockin reporter and multiple conditional deletion mouse models to show distinct differences in IL-15 expression between BM MSC subtypes. Conditional deletion of Il15 in Osx+ stromal cells results in decreased natural killer (NK) cell precursors, memory CD8+ T cells and NKT cells but not mature NK cells. Lepr+ stromal cells support the survival of mature NK cells and memory CD8+ T cells in the BM of older mice, while endothelial cells support mature NK cells and memory CD8+ T cells in the blood but not in the BM. Thus, our data suggest that MSC subtypes differentially regulate the development and survival of IL-15-dependent immune cell lineages in the BM.