Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems

Williams, Noelle S.; Klem, Jennifer; Puzanov, Igor; Sivakumar, Pallavur V.; Schatzle, John D.; Bennett, Michael V. L.; Kumar, Vinay

doi:10.1111/j.1600-065x.1998.tb01229.x

Cited by 117 publications

(87 citation statements)

References 124 publications

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“…For example, IL-15-deficient mice lack NK1.1 ϩ cells (3), indicating that IL-15 is essential for NK cell development in mice. The requirement of IL-15 for mouse NK cell development has also been demonstrated by other studies (4,5). In humans, IL-15 is considered to be required for in vitro NK cell development and virtually most current protocols for human NK cell differentiation culture depend on IL-15.…”

mentioning

confidence: 69%

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

Haraguchi

Suzuki²,

Koyama³

et al. 2009

The Journal of Immunology

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The development of NK cells from hematopoietic stem cells is thought to be dependent on IL-15. In this study, we demonstrate that stimulation of human cord blood CD34 ؉ cells by a Notch ligand, Delta4, along with IL-7, stem cell factor, and Fms-like tyrosine kinase 3 ligand, but no IL-15, in a stroma-free culture induced the generation of cells with characteristics of functional NK cells, including CD56 and CD161 Ag expression, IFN-␥ secretion, and cytotoxic activity against K562 and Jurkat cells. Addition of ␥-secretase inhibitor and anti-human Notch1 Ab to the culture medium almost completely blocked NK cell emergence. Addition of anti-human IL-15-neutralizing Ab did not affect NK cell development in these culture conditions. The presence of IL-15, however, augmented cytotoxicity and was required for a more mature NK cell phenotype. CD56 ؉ cells generated by culture with IL-15, but without Notch stimulation, were negative for CD7 and cytoplasmic CD3, whereas CD56 ؉ cells generated by culture with both Delta4 and IL-15 were CD7 ؉ and cytoplasmic CD3 ؉ from the beginning and therefore more similar to in vivo human NK cell progenitors. Together, these results suggest that Notch signaling is important for the physiologic development of NK cells at differentiation stages beyond those previously postulated.

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confidence: 69%

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

Haraguchi

Suzuki²,

Koyama³

et al. 2009

The Journal of Immunology

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“…As indicated by in vivo studies, patients who demonstrate Th2 dominance tend to develop chronic infection, whereas those with a Th1 phenotype can clear Of the ISGs analyzed, IL-15, a unique target of IRF-1, was also substantially reduced in both hepatic and T cells expressing either the entire HCV replicon or the structural proteins, and to our knowledge this is the first study reporting a repression of IL-15 in cells bearing the entire HCV replicon. IL-15 is involved in the activation and homeostatic maintenance of cells of both the innate and adaptive immune systems, playing a key role in CD8 ϩ T-cell homeostasis by promoting survival or proliferation of naive and memory phenotype CD8 T cells and in NK cell development, maturation, and survival (14,40,80). Notably, it has been reported that impaired IL-15 production is one of the mechanisms of the aberrant response of DC to IFN in HCV-infected patients (28).…”

Section: Discussionmentioning

confidence: 99%

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

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“…18,22 Neither IL-12 nor IL-18 seem to be essential for NK cell development, since both IL-12-deficient and IL-18-deficient mice show normal NK 1.1 þ cell development. 32 As is the case for IL-12-deficient and IL-18-deficient mice, the B6-mi/mi mice showed normal NK 1.1 þ cell development and significantly reduced NK activity. 9,10 However, in contrast to the IL-12-deficient and IL-18-deficient mice, the NK activity of B6-mi/mi mice was not recovered even after daily intraperitoneal injection of IL-18 (1000 ng) or IL-12 (100 ng) for 2 days, 22 (our unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Several cytokines play important roles in NK cell development and activity (reviewed in Williams et al 32 and Colucci et al 33 ). For example, Flt3 (FMS-like tyrosine kinase 3) ligand, 34 c-kit tyrosine kinase ligand, 35 and IL-7 36 are important for the early stages of NK cell development.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of IL-12 receptor β2 and IL-18 receptor α genes in natural killer cells and macrophages derived from B6-mi/mi mice

Kataoka

Komazawa

Oboki

et al. 2005

Laboratory Investigation

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The mi transcriptional factor (MITF) is a basic helix-loop-helix leucine zipper-type transcriptional factor. The mi mutant allele encodes an abnormal MITF, in which one out of four consecutive arginines is deleted in the basic domain. The VGA-9-tg (tg) allele is another mutant allele and considered to be a null mutant allele. C57BL/6 (B6)-mi/mi mice showed abnormal phenotypes of natural killer (NK) cells and macrophages, whereas B6-tg/tg mice did not. The expression levels of the genes for the interleukin-12 receptor (IL-12R) b2 and IL-18Ra were reduced in both the NK cells and macrophages of B6-mi/mi mice, while the expression levels of the corresponding genes in B6-tg/tg mice were unaffected. The B6-mi/mi NK cells and B6-mi/mi macrophages showed impaired responses to stimulation with IL-12, IL-18, and IL-12 plus IL-18 stimulation. The abnormal NK cell and macrophage of B6-mi/mi mice appear to be due to decreased expression of the IL-12Rb2 and IL-18Ra genes.

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Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems

Cited by 117 publications

References 124 publications

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Reduced expression of IL-12 receptor β2 and IL-18 receptor α genes in natural killer cells and macrophages derived from B6-mi/mi mice

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