scholarly journals Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Isabel Ohs ◽  
Maries van den Broek ◽  
Kathrin Nussbaum ◽  
Christian Münz ◽  
Sebastian J. Arnold ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Proinflammatory Cytokine ◽  
Nk Cell ◽  
Alternative Pathway ◽  
Killer Cell ◽  
Cell Development ◽  
Interleukin 12 ◽  
Gamma Chain ◽  
Common Gamma Chain

Abstract Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling.

scholarly journals A research-driven approach to the identification of novel natural killer cell deficiencies affecting cytotoxic function

Blood ◽  
2020 ◽  
Vol 135 (9) ◽  
pp. 629-637
Author(s):  
Michael T. Lam ◽  
Emily M. Mace ◽  
Jordan S. Orange
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Impact Testing ◽  
Primary Immune Deficiency ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

Abstract Natural killer cell deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent, or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro, and in vivo laboratory research. Evaluation involves initially quantifying NK cells and measuring NK cell cytotoxicity and expression of certain NK cell receptors involved in NK cell development and function. Subsequent studies using genomic methods to identify the potential causative variant are conducted along with variant impact testing to make genotype-phenotype connections. Identification of novel genes contributing to the NKD phenotype can also be facilitated by applying the expanding knowledge of NK cell biology. In this review, we discuss how NKDs that affect NK cell cytotoxicity can be approached in the clinic and laboratory for the discovery of novel gene variants.

scholarly journals The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2470-2477 ◽  
Author(s):  
Il-Kyoo Park ◽  
Chiara Giovenzana ◽  
Tiffany L. Hughes ◽  
Jianhua Yu ◽  
Rossana Trotta ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Absolute Number ◽  
Interferon Γ ◽  
Cell Development ◽  
Cytokine Signaling ◽  
Human Natural Killer Cell ◽  
Human Cd34

Interleukin-15 (IL-15) is essential for natural killer (NK) cell differentiation. In this study, we assessed whether the receptor tyrosine kinase Axl and its ligand, Gas6, are involved in IL-15–mediated human NK differentiation from CD34+ hematopoietic progenitor cells (HPCs). Blocking the Axl-Gas6 interaction with a soluble Axl fusion protein (Axl-Fc) or the vitamin K inhibitor warfarin significantly diminished the absolute number and percentage of CD3−CD56+ NK cells derived from human CD34+ HPCs cultured in the presence of IL-15, probably resulting in part from reduced phosphorylation of STAT5. In addition, CD3−CD56+ NK cells derived from culture of CD34+ HPCs with IL-15 and Axl-Fc had a significantly diminished capacity to express interferon-γ or its master regulator, T-BET. Culture of CD34+ HPCs in the presence of c-Kit ligand and Axl-Fc resulted in a significant decrease in the frequency of NK precursor cells responding to IL-15, probably the result of reduced c-Kit phosphorylation. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK-cell development, at least in part via its regulatory effects on both the IL-15 and c-Kit signaling pathways in CD34+ HPCs, and to functional NK-cell maturation via an effect on the master regulatory transcription factor T-BET.

scholarly journals Proinflammatory cytokine signaling required for the generation of natural killer cell memory

2012 ◽  
Vol 209 (5) ◽  
pp. 947-954 ◽  
Author(s):  
Joseph C. Sun ◽  
Sharline Madera ◽  
Natalie A. Bezman ◽  
Joshua N. Beilke ◽  
Mark H. Kaplan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Interleukin 12 ◽  
Cytokine Signaling ◽  
Mcmv Infection ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Memory Nk Cells

Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor–deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ–independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics.

scholarly journals Natural Killer Cell Regulation by MicroRNAs in Health and Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jeffrey W. Leong ◽  
Ryan P. Sullivan ◽  
Todd A. Fehniger
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Small Noncoding Rnas ◽  
Cellular Processes ◽  
Health And Disease ◽  
Effector Response ◽  
Insight Into

Natural killer (NK) cells are innate immune lymphocytes that are critical for normal host defense against infections and mediate antitumor immune responses. MicroRNAs (miRNAs) are a family of small, noncoding RNAs that posttranscriptionally regulate the majority of cellular processes and pathways. Our understanding of how miRNAs regulate NK cells biology is limited, but recent studies have provided novel insight into their expression by NK cells, and how they contribute to the regulation of NK cell development, maturation, survival, and effector function. Here, we review the expression of miRNAs by NK cells, their contribution to cell intrinsic and extrinsic control of NK cell development and effector response, and their dysregulation in NK cell malignancies.

scholarly journals Tumor growth impedes natural-killer-cell maturation in the bone marrow

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 246-252 ◽  
Author(s):  
John O. Richards ◽  
Xing Chang ◽  
Bradley W. Blaser ◽  
Michael A. Caligiuri ◽  
Pan Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Functional Maturation ◽  
Ifn Γ

Natural-killer (NK)-cell dysfunction and IFN-γ deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, breast cancer, colon cancer, and melanoma cell lines, interrupt functional maturation during NK-cell development in the bone marrow. The immature NK cells in the periphery of tumor-bearing mice had impaired IFN-γ production but seemingly normal cytotoxicity. T cells are not involved in this NK maturation arrest, because T-cell depletion did not restore NK-cell development. Moreover, the extent of tumor-cell infiltration into the bone marrow does not correlate with defective NK maturation. Interestingly, the defect was associated with a significant reduction in the IL-15Rα+ cells in the non-T, non-NK compartment of bone marrow cells and restored by overexpression of IL-15. Our data demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway. (Blood. 2006;108:246-252)

The Stage-Specific Effect of Interleukin-1 Beta (IL-1β) during Human Natural Killer Cell Development

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3746-3746
Author(s):  
Tiffany L Hughes ◽  
Michael Brian Becknell ◽  
Aharon Freud ◽  
Susan E Schmidt ◽  
Jianhua Yu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Messenger Rna ◽  
Nk Cell ◽  
Interleukin 1 ◽  
Killer Cell ◽  
Specific Effect ◽  
Cell Development ◽  
Human Natural Killer Cell ◽  
Survival Factor

Abstract Developmental intermediates of human natural killer (NK) cells are found within secondary lymphoid tissue (SLT), and five distinct stages of these intermediates have been identified. While it is well documented that developing NK cells are reliant on interleukin (IL)-15 as a survival factor, it is likely that additional cytokines and growth factors are required for complete NK cell differentiation. Microarray transcriptional profiling of purified stage 1–4 cells from human tonsil and stage 4 and 5 cells from peripheral blood (PB) identified a developmental window of interleukin-1 receptor 1 (IL-1R1) messenger RNA (mRNA) expression restricted to stages 2 and 3. We confirmed this finding by quantitative RT-PCR, and analysis of IL-1R1 surface protein expression revealed that, on average, 81% of stage 3 immature NK cells are IL-1R1(+), whereas the majority of cells from stages 1, 2, and 4 are IL-1R1(−). When cultured in vitro with IL-1β, a physiologic ligand for IL-1R1, cells from all four stages died within 48 hours, consistent with an absolute requirement for IL-15 as a survival factor. However, the combination of IL-1β and IL-15 led to a significant and reproducible 4.64±−0.68–fold increase in stage 3 cell number over that seen with IL-15 alone (p < 0.0005). This phenomenon was completely restricted to stage 3 immature NK cells, and is attributed to increased proliferation. The effects of IL-1β were abrogated by a molar excess of IL-1 receptor antagonist (IL-1RA), a physiologic competitor for IL-1R1 binding. Collectively, our data indicate that IL-1R1 expression fluctuates dramatically during NK cell development, and that unique responses of IL-1R1(+) stage 3 cells to IL-1β and IL-15 govern the expansion of these immature NK cells. Our findings support a model in which IL-1β promotes stage 3 proliferation and survival in vivo, driving stage 3 cells to be the most prevalent NK cell intermediates within SLT.

Interleukin-15 as an Activator of Natural Killer Cell-Mediated Antiviral Response

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4210-4219 ◽  
Author(s):  
Jean Gosselin ◽  
Andru TomoÏu ◽  
Robert C. Gallo ◽  
Louis Flamand
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanism ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Herpesvirus ◽  
Interleukin 12 ◽  
Target Cells ◽  
Antiviral Defense ◽  
Independent Manner

Natural killer (NK) cells are large granular lymphocytes capable of efficient killing of virus-infected and tumor cells in a major histocompatibility complex-independent manner. The cytotoxic killing potential of NK cells can be modulated by a variety of factors, including cytokines such as interleukin-12 (IL-12), IL-15, and interferon (IFN). IL-15 also plays an important role in NK cell development and survival. Killing of virally infected cells by NK cells is likely to represent an important antiviral defense mechanism, especially during the early phase of infection when antigen-specific immunity has yet to be generated. In the present work, we studied the potential of IL-15 to act as a modulator of NK cell-mediated antiviral defense. Our results clearly indicate that IL-15 can curtail infections by 3 human herpesviruses: Herpes simplex virus type 1, Epstein-Barr virus, and human herpesvirus 6. The antiviral activity of IL-15 is dose-, time-, and NK cell-dependent. IL-15–treated NK cells showed an increased killing potential against a variety of cells, including virus-infected target cells. Lastly, using highly purified cell population, we report that IL-15 triggers the synthesis of IFN-γ from both CD4+ and NK cells, which can act in both autocrine and paracrine fashion to modulate NK cells cytotoxic potential. In conclusion, IL-15 is a cytokine that can contribute to the establishment of an antiviral state in 2 ways: first by increasing the killing ability of NK cells and second by stimulating the synthesis and secretion of IFN.

scholarly journals Transcriptional Regulation of Natural Killer Cell Development and Functions

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1591 ◽  
Author(s):  
Dandan Wang ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Lymphocyte Subset ◽  
Innate Immune ◽  
Environmental Cues ◽  
Specific Manner

Natural killer (NK) cells are the major lymphocyte subset of the innate immune system. Their ability to mediate anti-tumor cytotoxicity and produce cytokines is well-established. However, the molecular mechanisms associated with the development of human or murine NK cells are not fully understood. Knowledge is being gained about the environmental cues, the receptors that sense the cues, signaling pathways, and the transcriptional programs responsible for the development of NK cells. Specifically, a complex network of transcription factors (TFs) following microenvironmental stimuli coordinate the development and maturation of NK cells. Multiple TFs are involved in the development of NK cells in a stage-specific manner. In this review, we summarize the recent advances in the understandings of TFs involved in the regulation of NK cell development, maturation, and effector function, in the aspects of their mechanisms, potential targets, and functions.

Interleukin-15 as an Activator of Natural Killer Cell-Mediated Antiviral Response

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4210-4219 ◽  
Author(s):  
Jean Gosselin ◽  
Andru TomoÏu ◽  
Robert C. Gallo ◽  
Louis Flamand
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanism ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Herpesvirus ◽  
Interleukin 12 ◽  
Target Cells ◽  
Antiviral Defense ◽  
Independent Manner

Abstract Natural killer (NK) cells are large granular lymphocytes capable of efficient killing of virus-infected and tumor cells in a major histocompatibility complex-independent manner. The cytotoxic killing potential of NK cells can be modulated by a variety of factors, including cytokines such as interleukin-12 (IL-12), IL-15, and interferon (IFN). IL-15 also plays an important role in NK cell development and survival. Killing of virally infected cells by NK cells is likely to represent an important antiviral defense mechanism, especially during the early phase of infection when antigen-specific immunity has yet to be generated. In the present work, we studied the potential of IL-15 to act as a modulator of NK cell-mediated antiviral defense. Our results clearly indicate that IL-15 can curtail infections by 3 human herpesviruses: Herpes simplex virus type 1, Epstein-Barr virus, and human herpesvirus 6. The antiviral activity of IL-15 is dose-, time-, and NK cell-dependent. IL-15–treated NK cells showed an increased killing potential against a variety of cells, including virus-infected target cells. Lastly, using highly purified cell population, we report that IL-15 triggers the synthesis of IFN-γ from both CD4+ and NK cells, which can act in both autocrine and paracrine fashion to modulate NK cells cytotoxic potential. In conclusion, IL-15 is a cytokine that can contribute to the establishment of an antiviral state in 2 ways: first by increasing the killing ability of NK cells and second by stimulating the synthesis and secretion of IFN.

scholarly journals TREM2 promotes natural killer cell development in CD3−CD122+NK1.1+ pNK cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hwa-Youn Lee ◽  
Eun-Hee Lee ◽  
Jawoon Yi ◽  
Kon-Young Ji ◽  
Su-Man Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Antitumor Effects ◽  
Hematopoietic Stem

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells. Results Here, we demonstrated for the first time that CD3−CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6 J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice. Conclusions Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

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