Suppressive Effect of a Standardized Mistletoe Extract on the Expression of Activatory NK Receptors and Function of Human NK Cells

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

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Maintenance and Function of Human CD8+ T Cells and NK Cells in Humanized Mice

Humanized Mice for HIV Research ◽

10.1007/978-1-4939-1655-9_15 ◽

2014 ◽

pp. 181-192

Author(s):

Udo F. Hartwig ◽

Maya C. André ◽

Christian Münz

Keyword(s):

T Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Humanized Mice ◽

And Function

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MicroRNA-27a-5p inhibits proliferation, migration and invasion and promotes apoptosis of Wilms tumor cell by targeting PBOV1

10.1101/2021.08.25.457737 ◽

2021 ◽

Author(s):

zhengtuan guo ◽

qiang yv ◽

chunlin miao ◽

wenan ge ◽

peng li

Keyword(s):

Tumor Cells ◽

Wilms Tumor ◽

Suppressive Effect ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tumor Tissues ◽

And Function ◽

Tumor Suppressive Effect

Wilms tumor is the most common type of renal tumor in children. MicroRNAs (miRNA) are small non-coding RNAs that play crucial regulatory roles in tumorigenesis. We aimed to study the expression profile and function of miR-27a-5p in Wilms tumor. MiR-27a-5p expression was downregulated in human Wilms tumor tissues. Functionally, overexpression of miR-27a-5p promoted cell apoptosis of Wilms tumor cells. Furthermore, upregulated miR-27a-5p delayed xenograft Wilms tumor tumorigenesis in vivo. Bioinformatics analysis predicted miR-27-5p directly targeted to the 3’-untranslated region (UTR) of PBOV1 and luciferase reporter assay confirmed the interaction between miR-27a-5p and PBOV1. The function of PBOV1 in Wilms tumor was evaluated in vitro and knockdown of PBOV1 dampened cell migration. In addition, overexpression of PBOV1 antagonized the tumor-suppressive effect of miR-27a-5p in Wilms tumor cells. Collectively, our findings reveal the regulatory axis of miR-27-5p/PBOV1 in Wilms tumor and miR-27a-5p might serve as a novel therapeutic target in Wilms tumor.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.732511 ◽

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.

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Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells

Cell Transplantation ◽

10.1177/0963689719872488 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1603-1613 ◽

Cited By ~ 1

Author(s):

Marcus Bergström ◽

Malin Müller ◽

Marie Karlsson ◽

Hanne Scholz ◽

Nils Tore Vethe ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Ex Vivo ◽

Mtor Inhibitors ◽

Allogeneic Transplantation ◽

Suppressive Effect ◽

And Function ◽

Treg Phenotype ◽

Suppression Assay

Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

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NK cells in treated HIV-infected children display altered phenotype and function

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2018.11.052 ◽

2019 ◽

Vol 144 (1) ◽

pp. 294-303.e13 ◽

Cited By ~ 4

Author(s):

Sanjana Mahapatra ◽

William T. Shearer ◽

Charles G. Minard ◽

Emily Mace ◽

Mary Paul ◽

...

Keyword(s):

Nk Cells ◽

And Function

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Characteristics of afferent fiber innervation on acupuncture points zusanli

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1983.245.4.r606 ◽

1983 ◽

Vol 245 (4) ◽

pp. R606-R612 ◽

Cited By ~ 7

Author(s):

G. W. Lu

Keyword(s):

Peroneal Nerve ◽

Afferent Fiber ◽

Suppressive Effect ◽

Structure And Function ◽

Acupuncture Points ◽

Digastric Muscle ◽

Movement Response ◽

Afferent Fibers ◽

And Function ◽

Peroneal Nerve Stimulation

Acupoint zusanli is one of the most effective points in traditional Chinese medicine. Needling point zusanli has a significant suppressive effect on jaw movement response (JMR) and electromyogram of digastric muscle (dEMG) induced by peroneal nerve stimulation. This effect is weakened or abolished by sectioning the peroneal nerve and blocking A-beta- and some A-delta-fibers in the nerve. When the point zusanli is stimulated electrically a larger-than-normal proportion of A-beta-fibers is activated. Local afferent fiber composition at this point contains more myelinated fibers, more large-sized fibers, and more A-beta-fibers than nonacupoints. This predominance of large afferent fibers in the composition and activity of point zusanli is thought to be one of the fundamental characteristics of the point in regard to its structure and function and contributes to its powerful acupuncture effect.

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Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2– versus IL-15–activated NK cells

Blood ◽

10.1182/blood-2006-07-037846 ◽

2007 ◽

Vol 109 (9) ◽

pp. 3767-3775 ◽

Cited By ~ 56

Author(s):

Laura Chiossone ◽

Chiara Vitale ◽

Francesca Cottalasso ◽

Sara Moretti ◽

Bruno Azzarone ◽

...

Keyword(s):

Nk Cells ◽

Cell Function ◽

Nk Cell ◽

Surface Expression ◽

Steroid Treatment ◽

Cross Linking ◽

Target Cells ◽

Activating Receptors ◽

And Function ◽

Nk Cytotoxicity

Abstract Steroids have been shown to inhibit the function of fresh or IL-2–activated natural killer (NK) cells. Since IL-15 plays a key role in NK-cell development and function, we comparatively analyzed the effects of methylprednisolone on IL-2– or IL-15–cultured NK cells. Methylprednisolone inhibited the surface expression of the major activating receptors NKp30 and NKp44 in both conditions, whereas NK-cell proliferation and survival were sharply impaired only in IL-2–cultured NK cells. Accordingly, methylprednisolone inhibited Tyr phosphorylation of STAT1, STAT3, and STAT5 in IL-2–cultured NK cells but only marginally in IL-15–cultured NK cells, whereas JAK3 was inhibited under both conditions. Also, the NK cytotoxicity was similarly impaired in IL-2– or IL-15–cultured NK cells. This effect strictly correlated with the inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity in a redirected killing assay against the FcRγ+ P815 target cells upon cross-linking of NKp46, NKG2D, or 2B4 receptors. In contrast, in the case of CD16, inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity were not impaired. Our study suggests a different ability of IL-15–cultured NK cells to survive to steroid treatment, thus offering interesting clues for a correct NK-cell cytokine conditioning in adoptive immunotherapy.

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