Natural killer–cell differentiation by myeloid progenitors

Abstract

IntroductionHematopoietic stem cells (HSCs) give rise to all blood lineages. 1 As HSCs differentiate along one lineage, they gradually lose the ability to develop into other lineages. 2 Hematopoietic differentiation involves lineage commitment, defined here as the initiation of developmental program(s) that lead to a particular cell fate. The accompanying inability to differentiate into other lineages has been referred to as lineage maintenance. 3 Lineage commitment and lineage maintenance are complementary processes that guide cell fate decisions. Thus, cells committed to a particular lineage have alternative developmental choices until lineage maintenance is complete. 4 Hematopoietic differentiation has been schematically depicted as a "tree of hematopoiesis," 1 outlining the possible developmental choices. According to this prevailing schema, the decision between lymphoid and myeloid lineages occurs very early. However, alternative views have been proposed, including the existence of a common myelo-lymphoid progenitor. 5,6 Elucidation of hematopoietic developmental pathways and extrinsic stimuli that influence them is instrumental to understanding both normal and malignant hematopoiesis. In particular, factors that favor natural killer (NK)-cell development could be used to exploit their activity against malignancies.NK cells are innate immune effector cells. Their derivation from either lymphoid or myeloid lineages was debated early in their discovery. 7 Further research showed that NK cells can be derived from common lymphoid progenitors (CLPs) and hence have been considered separate from myeloid lineage. 8,9 However, some studies question this and have shown that progenitors expressing myeloid antigens can develop into NK cells. 10,11 NKcell differentiation from hematopoietic progenitor cells (HPCs) can be studied in vitro. 12,13 This process depends on cytokines, notably interleukin-2 (IL-2) or IL-15, whereas other factors (stem cell factor [SCF], fms-like tyrosine kinase-3 ligand ) induce early HPC expansion and responsiveness to IL-2 and IL-15 signaling. 14 CD34 ϩ HPCs are heterogeneous and include cells at various levels of differentiation. Multipotent HPCs with long-term repopulation potential are contained within the CD34 ϩ CD38 Ϫ subset. 15 More advanced lineage precursors, included in the CD34 ϩ CD38 ϩ fraction, 15 have been categorized as common myeloid progenitor (CMP; CD34 ϩ CD38 ϩ CD123 ϩ CD45RA Ϫ ), granulocyticmonocytic precursor (GMP; (CD34 ϩ CD38 ϩ CD123 ϩ CD45RA ϩ ), and megakaryocyte-erythroid precursor (CD34 ϩ CD38 ϩ CD123 Ϫ CD45RA Ϫ ). 16 Subsets of CD34 ϩ precursors have also been distinguished by their ability to readily differentiate into NK cells. Surface receptors that define NK precursors include CD7, 13 CD122, 17 CD161, 18 integrin ␤7, and CD45RA high . 19 Stromal cell layers have been used to differentiate HPCs into NK cells. Sources of stroma include bone marrow, 13,20 murine fetal liver cell lines, 21 and human splenic fibroblasts. 22 Stroma increase the efficiency of NK-ce...

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

“…NK/T precursors will afterwards give rise to NK precursors (NKPs), and lastly immature NK (iNK) and mature NK cells. Nevertheless, there is currently a debate regarding other NK cell precursors; a recent study by Grzywacz et al 56 provided new insights into Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MRCC, metastatic renal cell carcinoma; NK, natural killer.…”

Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

“…others, the contribution of lymphoid [29] and myeloid [30] pathways to NK cell development from CD34 + stem cells is still a controversial issue. Additionally, it would be of interest to further characterize and directly compare ex vivo generated NK to the subsets of NK cells in PB to achieve a better understanding of the immunological and therapeutic properties of the generated cells.…”

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34+ precursors

“…In vitro models of NK-cell differentiation from CD34 + cell precursors may give rise to a heterogeneous ILC repertoire, and provide a useful tool to characterize factors that might modulate such process [28,[41][42][43]. In this context, we previously showed that IL-8 favors NK-cell differentiation, while IL-1β-releasing AML blasts may modulate CD161 + CD56 + cell differentiation, suggesting that inflammatory cytokines may influence such process [27,38].…”

“…IL-1β exerts its effects at early stages of differentiation, as revealed by the expression of LFA-1 and by the increase in ID2 and E4BP4 mRNA relative expression observed in CD34 + -derived precursors after only 4 days of culture. Finally, we show that IL-1β may exert a direct effect on LFA-1 − ILC3-like cells present in the cultures, inducing the acquisition of NK-cell markers, EOMES TF, cytolytic granules, and IFN-γ expression, paralleled by a decrease of RORγt TF.In vitro models of NK-cell differentiation from CD34 + cell precursors may give rise to a heterogeneous ILC repertoire, and provide a useful tool to characterize factors that might modulate such process [28,[41][42][43]. In this context, we previously showed that IL-8 favors NK-cell differentiation, while IL-1β-releasing AML blasts may modulate CD161 + CD56 + cell differentiation, suggesting that inflammatory cytokines may influence such process [27,38].…”