Cellular and molecular pathways in early stages of NK cell development
Abstract: Natural killer (NK) cells represent the third lymphoid lineage playing important role against viral infections and cancer. In contrast to B and T cell development where both cellular and regulatory pathways are well established, the development of NK cells from hematopoietic stem cells (HSCs) is poorly understood. Although bone marrow (BM) represents the main site for postnatal NK cell development, recently a distinct thymic-dependent NK cell pathway was identified, implicating a possible close link between NK and T cell development in adult hematopoiesis. To investigate whether a potential NK/T lineage restriction of multipotent progenitors might take place already in the BM, we examined the lineage potential of NK cell progenitors (NKPs) in adult BM. Notably, while Lin-CD122+NK1.1-DX5- NKPs fail to commit to the B and myeloid lineages, they sustain a combined NK and T cell potential, in vivo, and in vitro at the single cell level. Whereas T cell development from NK/T progenitors is Notch-dependent, their contribution to thymic and BM NK cells remains Notch-independent. These findings together demonstrate the existence of bi-potent NK/T cell progenitors in adult BM. The common cytokine receptor γ-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, their cellular targets as well as their complementary action remain 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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