scholarly journals The Volume Activated Potassium Channel KCNK5 is Up-Regulated in Activated Human T Cells, but Volume Regulation is Impaired

2016 ◽  
Vol 38 (3) ◽  
pp. 883-892 ◽  
Author(s):  
Signe S. Kirkegaard ◽  
Pernille Dyhl Strøm ◽  
Steen Gammeltoft ◽  
Anker Jon Hansen ◽  
Else K. Hoffmann
Keyword(s):  
T Cells ◽  
Potassium Channel ◽  
Regulatory Volume Decrease ◽  
Cell Physiology ◽  
Activated T Cells ◽  
Human T Cells ◽  
Activated T Cell ◽  
Multiple Sclerosis Patients ◽  
Pore Domain ◽  
Cl Permeability

Background/Aims: The potential role of the two-pore domain potassium channel KCNK5 (also known as TASK-2 and K2P5.1) in activated T cell physiology has only recently been described. So far KCNK5 has been described to be up-regulated in T cells in multiple sclerosis patients and to be implicated in the volume regulatory mechanism regulatory volume decrease (RVD) in T cells. Methods: We investigated the time-dependent expression pattern of KCNK5 in CD3/CD28 activated human T cells using qPCR and Western blotting and its role in RVD using a Coulter Counter. Results: KCNK5 is highly up-regulated in CD3/CD28 activated T cells both at mRNA (after 24 h) and protein level (72 and 144 h), but despite this up-regulation the RVD response is inhibited. Furthermore, the swelling-activated Cl- permeability in activated T cells is strongly decreased, and the RVD inhibition is predominantly due to the decreased Cl- permeability. Conclusion: The up-regulated KCNK5 in activated human T cells does not play a volume regulatory role, due to decreased Cl- permeability. We speculate that the KCNK5 up-regulation might play a role in hyperpolarization of the cell membrane leading to increased Ca2+ influx and proliferation of T cells.

scholarly journals Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis

2009 ◽  
Vol 206 (7) ◽  
pp. 1515-1523 ◽  
Author(s):  
Divya Purushothaman ◽  
Apurva Sarin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nadph Oxidase ◽  
Cell Apoptosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Activated T Cells ◽  
T Cell Apoptosis ◽  
Mitochondrial Superoxide ◽  
Activated T Cell

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91phox to characterize the molecular link to activated T cell apoptosis, we show that gp91phox-deficient T (T−/−) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase–dependent Bax activation and apoptosis. Activated T−/− cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.

scholarly journals iPABP, an inducible poly(A)-binding protein detected in activated human T cells.

1995 ◽  
Vol 15 (12) ◽  
pp. 6770-6776 ◽  
Author(s):  
H Yang ◽  
C S Duckett ◽  
T Lindsten
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Rna Binding ◽  
Binding Protein ◽  
Amino Acid Level ◽  
Binding Activity ◽  
Mrna Levels ◽  
Activated T Cells ◽  
Human T Cells

The poly(A)-binding protein (PABP) binds to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs. PABP is thought to play a role in both translation and mRNA stability. Here we describe the molecular cloning and characterization of an inducible PABP, iPABP, from a cDNA library prepared from activated T cells. iPABP shows 79% sequence identity to PABP at the amino acid level. The RNA binding domains of iPABP and PABP are nearly identical, while their C termini are more divergent. Like PABP, iPABP is primarily localized to the cytoplasm. iPABP is expressed at low levels in resting normal human T cells; following T-cell activation, however, iPABP mRNA levels are rapidly up-regulated. In contrast, PABP is constitutively expressed in both resting and activated T cells. iPABP mRNA was also expressed at much higher levels than PABP mRNA in heart and skeletal muscle tissue. These data suggest that the regulation of cytoplasmic poly(A)-binding activity is more complex than previously believed. In most tissues, poly(A)-binding activity is likely to be the result of the combined effects of constitutively expressed PABP and iPABP, whose expression is subject to more complex regulation.

E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII)

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2849-2857 ◽  
Author(s):  
Nienke van der Stoep ◽  
Edwin Quinten ◽  
Marisa Marcondes Rezende ◽  
Peter J. van den Elsen
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Regulatory Elements ◽  
Strong Reduction ◽  
Activated T Cells ◽  
Class Ii Transactivator ◽  
Human T Cells ◽  
E Box

Abstract In B cells, expression of CIITA and resulting major histocompatibility complex II (MHCII) is mediated exclusively by promoter III (CIITA-PIII) activation. Recent studies have established that CIITA-PIII also participates in the expression of CIITA in activated human T cells, dendritic cells, and monocytes. In this study we characterized the various regulatory elements and interacting factors of CIITA-PIII that account for specific activation in B lymphocytes. We identified 2 E-box motifs and an Ets/ISRE-consensus element (EICE) in CIITA-PIII as playing a crucial role in the B-cell-specific transcriptional regulation of CIITA. Abolishment of factor binding to these elements resulted in a strong reduction of CIITA-PIII activation in B cells only, whereas it did scarcely affect or not affect the activity of CIITA-PIII in activated T cells and monocytes. We show that in B cells, E47 and PU.1/IRF-4 interact with the E-box motifs and the EICE, respectively, and act synergistically in the activation of CIITA-PIII. Moreover, functional inhibition of either E47 or IRF-4 resulted in strong reduction of CIITA-PIII activity in B lymphocytes only. The finding that PU.1, IRF-4, and E47 play an important role in the B-cell-mediated activation of CIITA-PIII provides a link between antigen presentation functions and activation and differentiation events in B lymphocytes.

γδ T cell responses to activated T cells in multiple sclerosis patients induced by T cell vaccination

1998 ◽  
Vol 87 (1-2) ◽  
pp. 94-104 ◽  
Author(s):  
Piet Stinissen ◽  
Jingwu Zhang ◽  
Caroline Vandevyver ◽  
Guy Hermans ◽  
Jef Raus
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Γδ T Cell ◽  
Activated T Cells ◽  
Cell Responses ◽  
T Cell Vaccination ◽  
Multiple Sclerosis Patients

scholarly journals Quantitative Proteomics Reveals Protein Dysregulation During T Cell Activation in Multiple Sclerosis Patients Compared to Healthy Controls

2021 ◽  
Author(s):  
Chiara Cappelletti ◽  
Anna Maria Eriksson ◽  
Ina Skaara Brorson ◽  
Ingvild S. Leikfoss ◽  
Oda Glomstad Kråbøl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Susceptibility Genes ◽  
Healthy Controls ◽  
Activated T Cells ◽  
Multiple Sclerosis Patients

Abstract Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4 + T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4 + T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 hours prior to sampling. Electrospray liquid chromatographytandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1,801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4 + T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4 + T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.

scholarly journals Antigen-Induced Protective and Nonprotective Cell-Mediated Immune Components against Cryptococcus neoformans

1998 ◽  
Vol 66 (6) ◽  
pp. 2632-2639 ◽  
Author(s):  
Juneann W. Murphy ◽  
Fredda Schafer ◽  
Arturo Casadevall ◽  
Adekunle Adesina
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Interleukin 2 ◽  
Delayed Type Hypersensitivity ◽  
Survival Times ◽  
Activated T Cells ◽  
Activated T Cell ◽  
The Brain ◽  
Cell Profile

ABSTRACT Mice immunized with two different cryptococcal antigen preparations, one a soluble culture filtrate antigen (CneF) in complete Freund’s adjuvant (CFA) and the other heat-killed Cryptococcus neoformans cells (HKC), develop two different profiles of activated T cells. CneF-CFA induces CD4+ T cells responsible for delayed-type hypersensitivity (DTH) reactivity and for amplification of the anticryptococcal DTH response, whereas HKC induce CD4+ and CD8+ T cells involved in anticryptococcal DTH reactivity and activated T cells which directly kill C. neoformans cells. The main purpose of this study was to assess the level of protection afforded by each of the two different T-cell profiles against challenge with viable C. neoformans cells, thereby identifying which activated T-cell profile provides better protection. CBA/J mice immunized with CneF-CFA had significantly better protective responses, based on better clearance of C. neoformans from tissues, on longer survival times, and on fewer and smaller lesions in the brain, than HKC-immunized mice or control mice similarly infected with C. neoformans. Both immunization protocols induced an anticryptococcal DTH response, but neither induced serum antibodies to glucuronoxylmannan, so the protection observed in the CneF-CFA immunized mice was due to the activated T-cell profile induced by that protocol. HKC-immunized mice, which displayed no greater protection than controls, did not have the amplifier cells. Based on our findings, we propose that the protective anticryptococcal T cells are the CD4+ T cells which have been shown to be responsible for DTH reactivity and/or the CD4+ T cells which amplify the DTH response and which have been previously shown to produce high levels of gamma interferon and interleukin 2. Our results imply that there are protective and nonprotective cell-mediated immune responses and highlight the complexity of the immune response to C. neoformans antigens.

scholarly journals P03.02 Suppression of T-cell proliferation and cytokine release by the adenosine axis are mediated by different mechanisms

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A22.2-A23
Author(s):  
J Festag ◽  
T Thelemann ◽  
M Schell ◽  
S Raith ◽  
S Michel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Degradation Products ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
Human T Cells ◽  
Part Time ◽  
Ifn Γ ◽  
Cd73 Expression

BackgroundThe so-called adenosine axis has emerged as a promising therapeutic target pathway as high adenosine levels in the tumor microenvironment contribute to the suppression of antitumor immune responses. The ectonucleotidases CD39 and CD73 act in concert to degrade extracellular immune-stimulating adenosine triphosphate (ATP) to immunosuppressive adenosine. According to the current model, subsequent suppression of effector immune cell function is caused by binding of adenosine to adenosine receptors like the A2a receptor (A2aR). The ectonucleotidases CD39 and CD73 as well as the A2aR have emerged as molecular targets within the adenosine axis with currently more than 20 clinical trials investigating antitumor effects of CD39-, CD73- or A2aR blockade. We aimed to perform a direct comparison of these targets with regard to their roles in regulating T-cell proliferation and IFN-γ secretion.Materials and MethodsCD39 and CD73 expression was suppressed using LNAplusTM antisense oligonucleotides (ASOs). ASOs were synthesized as gapmers with flanking locked nucleic acids (LNA) to increase stability and affinity to the target RNA, leaving a central gap for recruitment of the RNA-degrading enzyme RNaseH I. Knockdown efficacy of ASOs on mRNA and protein level was investigated in primary human T cells. Furthermore, the effects of ATP, AMP and adenosine analogues on T–cell proliferation and IFN–γ secretion were investigated. A2aR was blocked using small molecule inhibitors that are currently under clinical investigation.ResultsTreatment of human T cells with LNA-modified ASOs specific for human CD39 and CD73 resulted in potent target knockdown in vitro without the use of a transfection reagent. T-cell proliferation was reduced after addition of ATP to activated T cells that was completely reverted by ASO-mediated suppression of CD39 and/or CD73 expression but not A2aR inhibition. Adenosine analogues inhibited IFN–γ secretion of activated T cells, however, they did not suppress T-cell proliferation. Blockade of the adenosine kinase was able to revert the anti-proliferative effect of ATP degradation products, arguing for downstream metabolites of adenosine, but not A2aR signaling, being responsible for the suppression of T-cell proliferation.ConclusionsCytokine secretion and proliferation of T cells might be differentially regulated by the adenosine axis. Adenosine might primarily affect cytokine secretion via A2aR signaling, whereas adenosine metabolites might especially impair proliferation of activated T cells independent from A2aR signaling. Therefore, inhibition of CD39 and/or CD73 holds exceptional advantages over A2aR blockade as both, A2aR dependent and A2aR independent effects of ATP degradation products are targeted simultaneously.Disclosure InformationJ. Festag: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. T. Thelemann: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. M. Schell: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. S. Raith: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. S. Michel: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. R. Klar: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG. F. Jaschinski: A. Employment (full or part-time); Significant; Secarna Pharmaceuticals GmbH & Co. KG.

scholarly journals Lymphokine regulation of CD45R expression on human T cell clones.

1989 ◽  
Vol 170 (6) ◽  
pp. 2147-2152 ◽  
Author(s):  
S A Brod ◽  
C E Rudd ◽  
M Purvee ◽  
D A Hafler
Keyword(s):  
Molecular Weight ◽  
T Cells ◽  
T Cell ◽  
Activated T Cells ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Human T Cells ◽  
Single Cell Cloning ◽  
Cell Expression

Whether the expression of higher molecular weight isoforms of the T-200 complex represents different lineages of T cells and/or a sequential stage of the differential pathway of T cells has been unclear. Understanding T cell expression of higher molecular weight isoforms of the T-200 complex (CD45R) may be important because of their association with regulation of immune responses. By direct single cell cloning, we observed a number of long-term T cell clones that expressed CD45RA (2H4). CD45RA expression could be further regulated by ionomycin or the cytokines IL-1 and IL-6, but not IL-2, IL-4, or IFN-gamma. These results indicate that CD45RA expression may define T cell lineages of activated T cells partially controlled by the cytokines IL-1 and IL-6. Further, these results may associate regulatory actions of IL-1 and IL-6 with their ability to increase CD45RA expression in subpopulations of human T cells.

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