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* Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden;
Microbiology, Tumor and Cell Biology (MTC), Strategic Research Center for Studies of Integrative Recognition in the Immune System (IRIS), Karolinska Institute, Stockholm, Sweden; and
Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom
Although bone marrow (BM) represents the main site for postnatal NK cell development, recently a distinct thymic-dependent NK cell pathway was identified. These studies were designed to investigate the role of cytokines in regulation of thymic NK cells and to compare with established regulatory pathways of BM-dependent NK cell compartment. The common cytokine receptor 
-chain (Il2rg) essential for IL-15-induced signaling, and FMS-like tyrosine kinase 3 (FLT3) receptor ligand (Flt3l) were previously identified as important regulatory pathways of the BM NK cell compartment based on lack of function studies in mice, however their complementary action remains unknown. By investigating mice double-deficient in Il2rg and Flt3l (Flt3l–/– Il2rg–/–), we demonstrate that FLT3L is important for IL2Rg-independent maintenance of both immature BM as well as peripheral NK cells. In contrast to IL-7, which is dispensable for BM but important for thymic NK cells, IL-15 has a direct and important role in both thymic and BM NK cell compartments. Although thymic NK cells were not affected in Flt3l–/– mice, Flt3l–/–Il2rg–/– mice lacked detectable thymic NK cells, suggesting that FLT3L is also important for IL-2Rg-independent maintenance of thymic NK cells. Thus, IL-2Rg cytokines and FLT3L play complementary roles and are indispensable for homeostasis of both BM and thymic dependent NK cell development, suggesting that the cytokine pathways crucial for these two distinct NK cell pathways are largely overlapping.
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1 These studies were supported by grants from: Swedish Cancer Society, Swedish Paediatric Cancer Society, Alfred Österlunds Foundation, Hemato-Linne and Swedish Medical Research Council. E.S. has an Assistant Professor position from the Swedish Cancer Society. H.N.C. is supported by the Iranian Ministry of Health. The Lund Stem Cell Center is supported by a Center of Excellence grant from the Swedish Foundation for Strategic Research. P.B., T.L., and P.H. belong to the IRIS Strategic Research Center at the Karolinska Institute, supported by the Swedish Foundation for Strategic Research.
E.S. and M.C. designed and conceptualized the research, analyzed the data and wrote the manuscript. M.C., H.N.C., Y.T., P.B., and T.L. did the phenotypic and functional characterization of different knockout mice and analyzed the data. S.E.W.J. and P.H. participated in the study design, data analysis, and writing of the manuscript.
2 M.C. and H.N.C. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Ewa Sitnicka, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden. E-mail address: ewa.sitnicka{at}med.lu.se
4 Abbreviations used in this paper: BM, bone marrow; CLP, common lymphoid progenitor; NKP, NK cell progenitor; FLT3, FMS-like tyrosine kinase-3; WT, wild type.
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