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

Introduction

The bone marrow (BM) stroma regulates hematopoiesis and provides specialized microenvironmental niches for the long-term survival of hematopoietic stem cells (HSC) and immunological memory. Stromal cells produce extracellular matrix to promote organ structure, but also express cytokines, chemokines and a distinct set of receptors, thereby promoting cell–cell interactions and cell positioning essential for hematopoiesis¹. Some of these lineage-instructive signals are the C-X-C motif chemokine ligand 12 (CXCL12), stem cell factor (SCF), interleukin (IL)-6, IL-7 and IL-15^{2, 3–4}. HSCs, for example, reside and self-renew in endothelial and perivascular niches formed by mesenchymal progenitors and endothelial cells (EC) that produce CXCL12 and SCF^{5, 6, 7–8}. Although CXCL12⁺ SCF⁺ BM mesenchymal stromal cells (MSC; including mesenchymal stem and progenitor cells as well as differentiated stromal cells) that support HSCs have been studied in great detail^{5, 6–7} and recent single-cell sequencing results indicate transcriptional heterogeneity among mouse BM MSCs^{9, 10–11}, the molecular and functional heterogeneity of interleukin 15 (IL-15) (co-)expressing MSC subsets remains less well understood.

IL-15 has been implicated in natural killer (NK) cell development¹² and type 1 innate lymphoid cell (ILC1) function¹³ as well as memory CD8⁺ T cell^{14, 15, 16–17} and NKT cell¹⁸ survival. Hematopoietic cells, in particular macrophages and dendritic cells, have long been considered to be the major source of IL-15 in the BM^14,19. However, several studies have suggested non-hematopoietic cells as a source of IL-15^{19, 20, 21–22} and combined deletion of IL-15Rα from macrophages and dendritic cells did not affect NK cell numbers in the BM¹⁴. In vitro experiments further indicate that stromal cells are required for NK cell development in the absence of exogenous IL-15²³, and CXCL12-CXCR4 signaling is essential for NK cell development in adult mice²⁴. These findings are in agreement with a study that used Il15-CFP knockin/knockout mice and identified IL-15⁺ BM stromal cells with a VCAM-1⁺ PDGFRβ^high CD31^– Sca-1^– phenotype²⁰. Together, these studies indicate that IL-15-expressing MSC subsets may provide unique niches essential for NK cell lineage specification, maturation and survival^25,26.

In addition to its role as a primary lymphoid organ, the BM is...