scholarly journals miR-150 regulates the development of NK and iNKT cells

2011 ◽  
Vol 208 (13) ◽  
pp. 2717-2731 ◽  
Author(s):  
Natalie A. Bezman ◽  
Tirtha Chakraborty ◽  
Timothy Bender ◽  
Lewis L. Lanier
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Substantial Reduction ◽  
Cell Lineage ◽  
Cell Development ◽  
Inkt Cell ◽  
Intrinsic Defect ◽  
Inkt Cells ◽  
Factor C ◽  
And Function

Natural killer (NK) and invariant NK T (iNKT) cells are critical in host defense against pathogens and for the initiation of adaptive immune responses. miRNAs play important roles in NK and iNKT cell development, maturation, and function, but the roles of specific miRNAs are unclear. We show that modulation of miR-150 expression levels has a differential effect on NK and iNKT cell development. Mice with a targeted deletion of miR-150 have an impaired, cell lineage–intrinsic defect in their ability to generate mature NK cells. Conversely, a gain-of-function miR-150 transgene promotes the development of NK cells, which display a more mature phenotype and are more responsive to activation. In contrast, overexpression of miR-150 results in a substantial reduction of iNKT cells in the thymus and in the peripheral lymphoid organs. The transcription factor c-Myb has been shown to be a direct target of miR-150. Our finding of increased NK cell and decreased iNKT cell frequencies in Myb heterozygous bone marrow chimeras suggests that miR-150 differentially controls the development of NK and iNKT cell lineages by targeting c-Myb.

scholarly journals Differential requirements for the Ets transcription factor Elf-1 in the development of NKT cells and NK cells

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1880-1887 ◽  
Author(s):  
Hak-Jong Choi ◽  
Yanbiao Geng ◽  
Hoonsik Cho ◽  
Sha Li ◽  
Pramod Kumar Giri ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Nk Cells ◽  
Nk Cell ◽  
Nkt Cells ◽  
Cell Development ◽  
Intrinsic Defect ◽  
Nkt Cell ◽  
Ets Family ◽  
And Function

Abstract E26 Transformation specific (Ets) family transcription factors control the expression of a large number of genes regulating hematopoietic cell development and function. Two such transcription factors, Ets-1 and myeloid Elf-1–like factor (MEF), have been shown to play critical roles in both natural killer (NK)– and NKT-cell development, but not in the development of conventional T cells. In this study, we address the role of E74-like factor 1 (Elf-1), another Ets family transcription factor that is closely related to MEF but divergent from Ets-1, in NK- and NKT-cell development using Elf-1–deficient (Elf-1−/−) mice. Whereas the proportion of NK cells in Elf-1−/− mice was normal, the proportion of NKT cells was significantly reduced in the thymus and periphery of Elf-1−/− mice compared with wild-type (WT) mice. Although Ets-1–deficient mice lack NKT cells altogether, Elf-1−/− mice exhibited only a partial block in NKT-cell development caused by a cell-intrinsic defect in the selection, survival, and maturation of NKT cells. In addition, residual NKT cells found in Elf-1−/− mice produced less cytokine upon antigen stimulation compared with WT NKT cells. Our data demonstrate that Elf-1 plays an important and nonredundant role in the development and function of NKT cells, but is not involved in NK-cell development.

scholarly journals SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

2019 ◽  
Vol 20 (19) ◽  
pp. 4797 ◽  
Author(s):  
Devika Bahal ◽  
Tanwir Hashem ◽  
Kim E. Nichols ◽  
Rupali Das
Keyword(s):  
Cell Biology ◽  
Current Knowledge ◽  
Cell Lineage ◽  
Cell Development ◽  
Inkt Cell ◽  
Functional Responses ◽  
Inkt Cells ◽  
Thymic Development ◽  
Signaling Axis ◽  
And Function

Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several immune cells. Thus, it is not surprising that iNKT cells play diverse roles in a broad range of diseases. Given their pivotal roles in host immunity, it is crucial that we understand the mechanisms that govern iNKT cell development and effector functions. Over the last two decades, several studies have contributed to the current knowledge of iNKT cell biology and activity. Collectively, these studies reveal that the thymic development of iNKT cells, their lineage expansion, and functional properties are tightly regulated by a complex network of transcription factors and signaling molecules. While prior studies have clearly established the importance of the SLAM-SAP-Fyn signaling axis in iNKT cell ontogenesis, recent studies provide exciting mechanistic insights into the role of this signaling cascade in iNKT cell development, lineage fate decisions, and functions. Here we summarize the previous literature and discuss the more recent studies that guide our understanding of iNKT cell development and functional responses.

scholarly journals Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1861-1871 ◽  
Author(s):  
Laura Hidalgo ◽  
Víctor G. Martínez ◽  
Jaris Valencia ◽  
Carmen Hernández-López ◽  
Miriam N. Vázquez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Lineage ◽  
Cell Types ◽  
Cell Development ◽  
Bmp Signaling ◽  
Type Ia ◽  
Nk Cell Differentiation

Abstract The bone morphogenetic protein (BMP) signaling pathway regulates survival, proliferation, and differentiation of several cell types in multiple tissues, including the thymus. Previous reports have shown that BMP signaling negatively regulates T-cell development. Here, we study the subpopulation of early human intrathymic progenitors expressing the type IA BMP receptor (BMPRIA) and provide evidence that CD34+CD1a−BMPRIA+ precursor cells mostly express surface cell markers and transcription factors typically associated with NK cell lineage. These CD34+ cells mostly differentiate into functional CD56+ natural killer (NK) cells when they are cocultured with thymic stromal cells in chimeric human-mouse fetal thymic organ cultures and also in the presence of SCF and IL-15. Moreover, autocrine BMP signaling can promote the differentiation of thymic NK cells by regulating the expression of key transcription factors required for NK cell lineage (eg, Id3 and Nfil3) as well as one of the components of IL-15 receptor, CD122. Subsequently, the resulting population of IL-15–responsive NK cell precursors can be expanded by IL-15, whose action is mediated by BMP signaling during the last steps of thymic NK cell differentiation. Our results strongly suggest that BMPRIA expression identifies human thymic NK cell precursors and that BMP signaling is relevant for NK cell differentiation in the human thymus.

scholarly journals Mitochondrial metabolism is essential for invariant natural killer T cell development and function

2021 ◽  
Vol 118 (13) ◽  
pp. e2021385118
Author(s):  
Xiufang Weng ◽  
Amrendra Kumar ◽  
Liang Cao ◽  
Ying He ◽  
Eva Morgun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cell Development ◽  
Mitochondrial Metabolism ◽  
Inkt Cell ◽  
Inkt Cells ◽  
And Function ◽  
Invariant Natural Killer

Conventional T cell fate and function are determined by coordination between cellular signaling and mitochondrial metabolism. Invariant natural killer T (iNKT) cells are an important subset of “innate-like” T cells that exist in a preactivated effector state, and their dependence on mitochondrial metabolism has not been previously defined genetically or in vivo. Here, we show that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP; T-Uqcrfs1−/−), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but no significant perturbation on the development of conventional T cells. The impaired development observed in T-Uqcrfs1−/− mice stems from a cell-autonomous defect in iNKT cells, resulting in a differentiation block at the early stages of iNKT cell development. Residual iNKT cells in T-Uqcrfs1−/− mice displayed increased apoptosis but retained the ability to proliferate in vivo, suggesting that their bioenergetic and biosynthetic demands were not compromised. However, they exhibited reduced expression of activation markers, decreased T cell receptor (TCR) signaling and impaired responses to TCR and interleukin-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATc2 activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in iNKT cell development and activation outside of its traditional role in supporting cellular bioenergetic demands.

scholarly journals The Role of microRNAs in NK Cell Development and Function

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2020
Author(s):  
Arash Nanbakhsh ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Cell Development ◽  
Clinical Use ◽  
Effector Functions ◽  
Genetic Manipulations ◽  
Cytotoxic Proteins ◽  
And Function

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions.

Involvement of NFAT Signaling in Function and Anti-Tumor Reactivity of NK Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1887-1887
Author(s):  
Julia S Wild ◽  
Benjamin J Schmiedel ◽  
Melanie Märklin ◽  
Lothar Kanz ◽  
Martin R Müller ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Clinical Success ◽  
Immunosuppressive Treatment ◽  
Cell Development ◽  
Lymphoid Cells ◽  
Inosine Monophosphate Dehydrogenase ◽  
And Function

Abstract Abstract 1887 NK cells play an important role in anti-tumor immunity. They significantly contribute to the clinical success of allogeneic stem cell transplantation (SCT). Their reactivity as a consequence of an integrative response mediated by various activating and inhibitory surface receptors results in the induction of yet only partially defined signal transduction pathways. One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells). While its role in T cell development and function is meanwhile well defined, surprisingly little is known on its function in NK cells. NFAT seems to be dispensable for NK cell development, but several lines of evidence clearly point to its involvement in NK reactivity and function. Cyclosporin A (CsA) and tacrolimus are immunosuppressive drugs that are widely used in transplant medicine. They mediate their immunosuppressive effects through inhibition of the serine/threonine phosphatase calci-neurin, which dephosphorylates and thereby activates NFAT. Here we studied the role of NFAT in NK cells and found that all five NFAT family members are expressed in NK cells with their levels being dependent on NK cell activation state. CsA and tacrolimus, but not mycophenolic acid which mediates its immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase, reduced activation and degranulation of NK cells, resulting in impaired cytotoxicity and IFN-γ production in response to leukemia targets. NK reactivity was also suppressed by the specific NFAT inhibitors VIVIT and INCA-6, indicating that the calcineurin inhibitors CsA and tacrolimus in fact modulate NK reactivity by inhibition of NFAT proteins and not by potential “off target”-effects. These results provide evidence for the critical involvement of the transcription factor NFAT in NK cell reactivity and also indicate that potential effects on NK cell immunosurveillance should be considered upon choice and dosing of immunosuppressive treatment regimens after SCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3245-3253 ◽  
Author(s):  
Frank Cichocki ◽  
Rebecca J. Hanson ◽  
Todd Lenvik ◽  
Michelle Pitt ◽  
Valarie McCullar ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Target Cells ◽  
Promoter Element ◽  
Kir Genes ◽  
Factor C ◽  
Distal Promoter ◽  
Kir Gene

Abstract The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5′ promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education.

A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1565-1573 ◽  
Author(s):  
Eva Eckelhart ◽  
Wolfgang Warsch ◽  
Eva Zebedin ◽  
Olivia Simma ◽  
Dagmar Stoiber ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Development ◽  
Tumor Control ◽  
Transgenic Mouse Line ◽  
Survival And Development ◽  
And Function

Abstract We generated a transgenic mouse line that expresses the Cre recombinase under the control of the Ncr1 (p46) promoter. Cre-mediated recombination was tightly restricted to natural killer (NK) cells, as revealed by crossing Ncr1-iCreTg mice to the eGFP-LSLTg reporter strain. Ncr1-iCreTg mice were further used to study NK cell–specific functions of Stat5 (signal transducers and activators of transcription 5) by generating Stat5f/fNcr1-iCreTg animals. Stat5f/fNcr1-iCreTg mice were largely devoid of NK cells in peripheral lymphoid organs. In the bone marrow, NK-cell maturation was abrogated at the NK cell–precursor stage. Moreover, we found that in vitro deletion of Stat5 in interleukin 2–expanded NK cells was incompatible with NK-cell viability. In vivo assays confirmed the complete abrogation of NK cell–mediated tumor control against B16F10-melanoma cells. In contrast, T cell–mediated tumor surveillance against MC38-adenocarcinoma cells was undisturbed. In summary, the results of our study show that STAT5 has a cell-intrinsic role in NK-cell development and that Ncr1-iCreTg mice are a powerful novel tool with which to study NK-cell development, biology, and function.

scholarly journals Mouse natural killer cell development and maturation are differentially regulated by SHIP-1

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4583-4590 ◽  
Author(s):  
Cindy Banh ◽  
S. M. Shahjahan Miah ◽  
William G. Kerr ◽  
Laurent Brossay
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
Inositol Phosphatase ◽  
Ifn Γ ◽  
Phosphoinositide 3 Kinase ◽  
Activation Motif

Abstract The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5′ inositol phosphatase known to negatively regulate the product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol-3.4,5-trisphosphate. SHIP-1 can be recruited to a large number of inhibitory receptors expressed on natural killer (NK) cells. However, its role in NK cell development, maturation, and functions is not well defined. In this study, we found that the absence of SHIP-1 results in a loss of peripheral NK cells. However, using chimeric mice we demonstrated that SHIP-1 expression is not required intrinsically for NK cell lineage development. In contrast, SHIP-1 is required cell autonomously for NK cell terminal differentiation. These findings reveal both a direct and indirect role for SHIP-1 at different NK cell development checkpoints. Notably, SHIP-1–deficient NK cells display an impaired ability to secrete IFN-γ during cytokine receptor–mediated responses, whereas immunoreceptor tyrosine–based activation motif containing receptor-mediated responses is not affected. Taken together, our results provide novel insights on how SHIP-1 participates in the development, maturation, and effector functions of NK cells.

scholarly journals Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 130-142 ◽  
Author(s):  
Molly F. Thomas ◽  
Sarah Abdul-Wajid ◽  
Marisella Panduro ◽  
Joshua E. Babiarz ◽  
Misha Rajaram ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Selective Reduction ◽  
Cell Development ◽  
Intrinsic Defect ◽  
Mcmv Infection ◽  
Activating Receptors ◽  
Antiviral Function

AbstractNatural killer (NK) cells play a critical role in early host defense to infected and transformed cells. Here, we show that mice deficient in Eri1, a conserved 3′-to-5′ exoribonuclease that represses RNA interference, have a cell-intrinsic defect in NK-cell development and maturation. Eri1−/− NK cells displayed delayed acquisition of Ly49 receptors in the bone marrow (BM) and a selective reduction in Ly49D and Ly49H activating receptors in the periphery. Eri1 was required for immune-mediated control of mouse CMV (MCMV) infection. Ly49H+ NK cells deficient in Eri1 failed to expand efficiently during MCMV infection, and virus-specific responses were also diminished among Eri1−/− T cells. We identified miRNAs as the major endogenous small RNA target of Eri1 in mouse lymphocytes. Both NK and T cells deficient in Eri1 displayed a global, sequence-independent increase in miRNA abundance. Ectopic Eri1 expression rescued defective miRNA expression in mature Eri1−/− T cells. Thus, mouse Eri1 regulates miRNA homeostasis in lymphocytes and is required for normal NK-cell development and antiviral immunity.

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