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 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 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 Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

scholarly journals T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Kiekens ◽  
Wouter Van Loocke ◽  
Sylvie Taveirne ◽  
Sigrid Wahlen ◽  
Eva Persyn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Current Knowledge ◽  
Functional Differentiation ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
And Function

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

scholarly journals Vascular Endothelial Cell Biology: An Update

2019 ◽  
Vol 20 (18) ◽  
pp. 4411 ◽  
Author(s):  
Krüger-Genge ◽  
Blocki ◽  
Franke ◽  
Jung
Keyword(s):  
Endothelial Cells ◽  
Cell Biology ◽  
Current Knowledge ◽  
Regional Blood Flow ◽  
Vascular Endothelial Cell ◽  
Inflammatory Cells ◽  
The Body ◽  
Arterial Tree ◽  
Foreign Materials ◽  
And Function

The vascular endothelium, a monolayer of endothelial cells (EC), constitutes the inner cellular lining of arteries, veins and capillaries and therefore is in direct contact with the components and cells of blood. The endothelium is not only a mere barrier between blood and tissues but also an endocrine organ. It actively controls the degree of vascular relaxation and constriction, and the extravasation of solutes, fluid, macromolecules and hormones, as well as that of platelets and blood cells. Through control of vascular tone, EC regulate the regional blood flow. They also direct inflammatory cells to foreign materials, areas in need of repair or defense against infections. In addition, EC are important in controlling blood fluidity, platelet adhesion and aggregation, leukocyte activation, adhesion, and transmigration. They also tightly keep the balance between coagulation and fibrinolysis and play a major role in the regulation of immune responses, inflammation and angiogenesis. To fulfill these different tasks, EC are heterogeneous and perform distinctly in the various organs and along the vascular tree. Important morphological, physiological and phenotypic differences between EC in the different parts of the arterial tree as well as between arteries and veins optimally support their specified functions in these vascular areas. This review updates the current knowledge about the morphology and function of endothelial cells, particularly their differences in different localizations around the body paying attention specifically to their different responses to physical, biochemical and environmental stimuli considering the different origins of the EC.

scholarly journals bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

1996 ◽  
Vol 183 (2) ◽  
pp. 381-391 ◽  
Author(s):  
D A Grillot ◽  
R Merino ◽  
J C Pena ◽  
W C Fanslow ◽  
F D Finkelman ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Immunoglobulin M ◽  
Protective Mechanism ◽  
And Function ◽  
Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

scholarly journals MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tingting Liu ◽  
Jie Wang ◽  
Kalpana Subedi ◽  
Qijun Yi ◽  
Li Zhou ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
Loss Of Function ◽  
Mait Cells ◽  
Cellular Processes ◽  
Individual Mirnas ◽  
Maturation Stages ◽  
And Function ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

Asymmetric Allospecific Signals Shape iNKT Cell Lineage Fate Decisions

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4274-4274
Author(s):  
Beverly SI Strong ◽  
Tess J Newkold ◽  
Amanda E Lee ◽  
Lucas E Turner ◽  
Jonathon W Heusel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Allogeneic Bone Marrow Transplantation ◽  
Flow Cytometric Analysis ◽  
Cell Lineage ◽  
Inkt Cell ◽  
Allogeneic Bone ◽  
C Cells ◽  
Inkt Cells ◽  
The Impact

Abstract Invariant NKT (iNKT) cells are glycolipid-reactive alpha/beta T cells which have an important role in the regulation of GVHD after allogeneic bone marrow transplantation. During thymic development, murine iNKT cells divide into three transcriptionally distinct lineages-NKT1, NKT2, and NKT17 that differ in their cytokine expression profile both at rest and upon antigen recognition via their TCR. Given that the lineage profile of iNKT cells varies dramatically between inbred strains of mice, it has been postulated that recognition of allospecific glycolipids determines iNKT cell lineage-fate decisions. Therefore, we challenged this hypothesis in a murine model of prenatal allogeneic transplantation to determine if the lineage commitment of immature iNKT cells was intrinsically programmed or extrinsically regulated by the allospecific environment during development. Prenatal allogeneic chimeras were established by in utero transplantation of E14 fetal liver light density cells into age-matched allogeneic fetal recipients (Balb/c to B6 or B6 to Balb/c). In this model, immature iNKT cells of both donor and host origin have the capacity to participate in education as CD1d on bone marrow-derived cells regulate the maturation of developing iNKT cells. This permitted an analysis of the impact of either host-to-donor or donor-to-host environmental cues in directing iNKT cell lineage-fate decisions. iNKT cell populations were identified using flow cytometric analysis of the transcription factors PLZF and T-bet. The lineage profile for donor and host thymic iNKT cells from chimeric mice were compared to the thymic iNKT cell population in naïve controls. As shown, B6 iNKT cells in prenatal chimeras exhibited a predominance of the NKT1 lineage in either the donor or the host situation similar to their frequency in naïve B6 controls (figure A). Conversely, Balb/c iNKT cells in both the donor and the host situation exhibited skewing toward an NKT1 lineage profile and away from the NKT2 lineage bias seen in naïve Balb/c controls (figure B). Furthermore, the expression of the H-2d MHC class I-reactive Ly49A receptor by Balb/c iNKT cells strongly correlates with the NKT1 lineage fate in control animals. However, both donor and host Balb/c cells demonstrated reduced correlation between Ly49A expression and NKT1 lineage fate indicating that the presence of H-2b expressing B6 cells diminished the ability of H-2d -reactive Ly49A to dictate lineage fate decisions. This study uniquely demonstrates the potential for cell-extrinsic signals in guiding iNKT cell lineage fate in an asymmetric fashion. Specifically, we find that: 1) the B6 iNKT lineage profile is intrinsically determined and unaffected by exposure to allogeneic Balb/c cells during development; 2) the Balb/c iNKT cell lineage profile is extrinsically determined and dominantly skewed toward an NKT1 lineage by exposure to even small numbers of B6 cells during development; and 3) the exposure to B6 cells overrides the contribution of Ly49A to developmental decisions made by Balb/c iNKT cells. Future studies will explore the regulatory interactions that govern allospecific iNKT cell lineage fate decisions and the resulting impact on the pro-inflammatory or immunoregulatory function of iNKT cells in clinically-relevant models. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phospholipase Cγ1 is essential for T cell development, activation, and tolerance

2010 ◽  
Vol 207 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Guoping Fu ◽  
Yuhong Chen ◽  
Mei Yu ◽  
Andy Podd ◽  
James Schuman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Phospholipase Cγ1 ◽  
T Cell Biology ◽  
Single Positive ◽  
And Function

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance.

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