Prolonged expression of CD154 on CD4 T cells from pediatric lupus patients correlates with increased CD154 transcription, increased nuclear factor of activated T cell activity, and glomerulonephritis

Mehta, Jay; Genin, Anna; Brunner, Michael; Scalzi, Lisabeth V.; Mishra, Nilamadhab; Beukelman, Timothy; Cron, Randy Q.

doi:10.1002/art.27554

Cited by 19 publications

(33 citation statements)

References 72 publications

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“…Also, we could show that the increase in CD40L expression during T cell activation could be remarkably abrogated by Kv1.3-NPs. The inhibition of CD40L by Kv1.3-NPs is consistent with studies showing that CD40L increased expression in SLE T cells is reduced by suppression of Ca 2+ influx with inhibitors such as cyclosporine, especially when they are added at the early stages of stimulation [1, 6, 7, 34]. Since the effect of Kv1.3-NPs is observed when T cells are stimulated with TG, this indicates that suppressing Ca 2+ influx is sufficient to downregulate CD40L expression in T cells.…”

Section: Discussionsupporting

confidence: 85%

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Chimote

Hajdú

Kottyan

et al. 2016

Journal of Autoimmunity

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Ca2+ signaling controls activation and effector functions of T lymphocytes. Ca2+ levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro-inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca2+ signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO+ memory T cells and reduce the activation-induced Ca2+ influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO+ T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naïve. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.

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Section: Discussionsupporting

confidence: 85%

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Chimote

Hajdú

Kottyan

et al. 2016

Journal of Autoimmunity

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“…For example, minocycline is a potential trigger of drug-induced lupus, and recent studies demonstrate a clear association between increased NFAT1 activity in T cells and systemic lupus erythematosus (55)(56)(57)(58). Paradoxically, in cases of minocyclineinduced lupus, higher doses might prove therapeutic through increased suppression of NFAT1.…”

Section: Discussionmentioning

confidence: 99%

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Szeto¹,

Pomerantz

Graham

et al. 2011

Journal of Biological Chemistry

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Minocycline is a tetracycline family antibiotic that has antiinflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4 ؉ T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4 ؉ T cell activation:NF-B, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca 2؉ flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4 ؉ T cell activation and may better inform the application of minocycline as an immunomodulatory agent.The tetracycline family of antibiotics is known to have multiple biological activities distinct from their antimicrobial function. Over the past two decades, the tetracycline derivative minocycline has demonstrated neuroprotective and immunomodulatory effects in animal models of diseases, including multiple sclerosis and Parkinson and Huntington diseases (1-3). Interest in the mechanism of its neuroprotective abilities has driven extensive research on minocycline-induced effects on inflammatory signaling in monocyte lineage cells, particularly the brain-resident microglia (4 -6). Modulation of T cell activation and function has also been proposed as one of the major mechanisms of action of minocycline.T cell activation contributes to disease pathogenesis by creating an inflammatory environment that leads to cellular damage and death as well as decreased immune function. Minocycline has been found to be therapeutic in multiple diseases whose pathogenesis is significantly T cell driven by modulating cellular activation and function. In rheumatoid arthritis patients, minocycline significantly improved clinical symptoms and increased the frequency of remissions leading to its usage as a disease modifying anti-rheumatic drug (7-9). Studies using CD4 ϩ T cell clones derived from the synovium of an rheumatoid arthritis patient showed that minocycline decreased activation-induced proliferation and inflammatory cytokine production (10). Minocycline has also shown therapeutic effects on T cells in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Minocycline treatment of rodents with experimental autoimmune encephalomyelitis attenuated the severity of encephalitis, decreased T cell transmigration in vitro, and reduced CD4...

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“…It has been widely used to transfer DNA or RNA into dozens of primary cell types of different species, including human primary CD4 T cells. More than 100 research papers have been published using Nucleofection ® for gene transfer into primary human T cells (Tahvanainen et al, 2006; Magg et al, 2009; Torgerson et al, 2009) on a range of topics, including T cell activation (Finney et al, 2004; Zhao et al, 2005; Stallwood et al, 2006), signal transduction (Kovacs et al, 2005; Methi et al, 2005; Wabnitz et al, 2006), transcriptional regulation (Grant et al, 2006; Mantel et al, 2006; Mehta et al, 2010), and HIV-1 infection (Chiu et al, 2005; Trushin et al, 2005; Selliah et al, 2008). More recently, this technology has been popularized for selectively knocking down, or silencing, gene expression in primary human CD4 T cells (Zhang et al, 2012; Freeley and Long, 2013).…”

Section: Introductionmentioning

confidence: 99%

The impact of Nucleofection® on the activation state of primary human CD4 T cells

Zhang

Selliah³

et al. 2014

Journal of Immunological Methods

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Gene transfer into primary human CD4 T lymphocytes is a critical tool in studying the mechanism of T cell-dependent immune responses and human immunodeficiency virus-1 (HIV-1) infection. Nucleofection® is an electroporation technique that allows efficient gene transfer into primary human CD4 T cells that are notoriously resistant to traditional electroporation. Despite its popularity in immunological research, careful characterization of its impact on the physiology of CD4 T cells has not been documented. Herein, using freshly-isolated primary human CD4 T cells, we examine the effects of Nucleofection® on CD4 T cell morphology, intracellular calcium levels, cell surface activation markers, and transcriptional activity. We find that immediately after Nucleofection®, CD4 T cells undergo dramatic morphological changes characterized by wrinkled and dilated plasma membranes before recovering 1 hour later. The intracellular calcium level also increases after Nucleofection®, peaking after 1 hour before recovering 8 hours post transfection. Moreover, Nucleofection® leads to increased expression of T cell activation markers, CD154 and CD69, for more than 24 hours, and enhances the activation effects of phytohemagglutinin (PHA) stimulation. In addition, transcriptional activity is increased in the first 24 hours after Nucleofection®, even in the absence of exogenous stimuli. Therefore, Nucleofection® significantly alters the activation state of primary human CD4 T cells. The effect of transferred gene products on CD4 T cell function by Nucleofection® should be assessed after sufficient resting time post transfection or analyzed in light of the activation caveats mentioned above.

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Prolonged expression of CD154 on CD4 T cells from pediatric lupus patients correlates with increased CD154 transcription, increased nuclear factor of activated T cell activity, and glomerulonephritis

Cited by 19 publications

References 72 publications

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

The impact of Nucleofection® on the activation state of primary human CD4 T cells

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