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

Carmen Stecher, Romana Bischl, Anna Schmid-Böse, Stefanie Ferstl, Elisabeth Potzmann, Magdalena Frank, Nina Braun, Matthias Farlik, Richard A. Flavell and Dietmar Herndler-Brandstetter ()
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Carmen Stecher: Medical University of Vienna and Comprehensive Cancer Center
Romana Bischl: Medical University of Vienna and Comprehensive Cancer Center
Anna Schmid-Böse: Medical University of Vienna and Comprehensive Cancer Center
Stefanie Ferstl: Medical University of Vienna and Comprehensive Cancer Center
Elisabeth Potzmann: Medical University of Vienna and Comprehensive Cancer Center
Magdalena Frank: Medical University of Vienna and Comprehensive Cancer Center
Nina Braun: Medical University of Vienna and Comprehensive Cancer Center
Matthias Farlik: Medical University of Vienna and Comprehensive Cancer Center
Richard A. Flavell: Howard Hughes Medical Institute
Dietmar Herndler-Brandstetter: Medical University of Vienna and Comprehensive Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61231-0

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