Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

Human natural killer (NK) cells originate from CD34(+) hematopoietic progenitor cells, but the discrete stages of NK cell differentiation in vivo have not been elucidated. We identify and functionally characterize, from human lymph nodes and tonsils, four NK cell developmental intermediates spanning the continuum of differentiation from a CD34(+) NK cell progenitor to a functionally mature NK cell. Analyses of each intermediate stage for CD34, CD117, and CD94 cell surface expression, lineage differentiation potentials, capacity for cytokine production and natural cytotoxicity, and ETS-1, GATA-3, and T-BET expression provide evidence for a new model of human NK cell differentiation in secondary lymphoid tissues.

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Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells

Blood ◽

10.1182/blood-2006-04-020198 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3824-3833 ◽

Cited By ~ 107

Author(s):

Bartosz Grzywacz ◽

Nandini Kataria ◽

Magdalena Sikora ◽

Robert A. Oostendorp ◽

Elaine A. Dzierzak ◽

...

Keyword(s):

Cell Differentiation ◽

Natural Killer ◽

Cell Line ◽

Nk Cell ◽

Fetal Liver ◽

Interferon Γ ◽

Intermediate Phenotype ◽

Interleukin 7 ◽

Nk Cell Differentiation ◽

And Function

AbstractThe stages of human natural killer (NK) cell differentiation are not well established. Culturing CD34+ progenitors with interleukin 7 (IL-7), IL-15, stem cell factor (SCF), FLT-3L, and murine fetal liver cell line (EL08.1D2), we identified 2 nonoverlapping subsets of differentiating CD56+ cells based on CD117 and CD94 (CD117highCD94– and CD117low/–CD94+ cells). Both populations expressed CD161 and NKp44, but differed with respect to NKp30, NKp46, NKG2A, NKG2C, NKG2D, CD8, CD16, and KIR. Only the CD117low/– CD94+ population displayed cytotoxicity and interferon-γ production. Both populations arose from a single CD34+CD38– Lin– cell and their percentages changed over time in a reciprocal fashion, with CD117highCD94– cells predominating early and decreasing due to an increase of the CD117low/–CD94+ population. These 2 subsets represent distinct stages of NKcell differentiation, since purified CD117high CD94– cells give rise to CD117low/–CD94+ cells. The stromal cell line (EL08.1D2) facilitated the transition from CD117highCD94– to CD117low/–CD94+ via an intermediate phenotype (CD117lowCD94low/–). EL08.1D2 also maintained the mature phenotype, preventing the reversion of CD117low/–CD94+ cells to the intermediate (CD117lowCD94low/–) phenotype. An analogous population of CD56+CD117highCD94– cells was found in cord blood. The identified stages of NK-cell differentiation provide evidence for coordinated acquisition of HLA-specific inhibitory receptors (ie, CD94/NKG2A) and function in developing human NK cells.

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Faculty Opinions recommendation of Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739581058.793584198 ◽

2021 ◽

Author(s):

Francesco Colucci

Keyword(s):

Cell Differentiation ◽

Nk Cell ◽

Nk Cell Differentiation ◽

Endometrial Regeneration

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Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

BioEssays ◽

10.1002/bies.202100281 ◽

2022 ◽

pp. 2100281

Author(s):

Jiang Zhang ◽

Noémi Rousseaux ◽

Thierry Walzer

Keyword(s):

Cell Differentiation ◽

Nk Cell ◽

Nk Cell Differentiation

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The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation

Blood ◽

10.1182/blood.2020005204 ◽

2020 ◽

Author(s):

Sylvie Taveirne ◽

Sigrid Wahlen ◽

Wouter Van Loocke ◽

Laura Kiekens ◽

Eva Persyn ◽

...

Keyword(s):

Transcription Factor ◽

Cell Differentiation ◽

Cell Biology ◽

Nk Cell ◽

Embryonic Stem ◽

Terminal Differentiation ◽

Cell Development ◽

Immune Defense ◽

Nk Cell Differentiation ◽

Important Regulator

Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and regulate other immune cells by cytokine secretion. Whereas murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells (hESC) and by expressing the dominant-negative ETS1 p27 isoform in cord blood (CB) hematopoietic progenitor cells (HPCs), we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation, i.e. E4BP4, TXNIP, TBET, GATA3, HOBIT and BLIMP1. In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation.

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