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Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.

Overview of attention for article published in Journal of Neuroinflammation, January 2015
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3 tweeters

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Title
Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.
Published in
Journal of Neuroinflammation, January 2015
DOI 10.1186/s12974-015-0460-z
Pubmed ID
Authors

Mazzola, Maria Antonietta, Raheja, Radhika, Murugaiyan, Gopal, Rajabi, Hasan, Kumar, Deepak, Pertel, Thomas, Regev, Keren, Griffin, Russell, Aly, Lilian, Kivisakk, Pia, Nejad, Parham, Patel, Bonny, Gwanyalla, Nguendab, Hei, Hillary, Glanz, Bonnie, Chitnis, Tanuja, Weiner, Howard L, Gandhi, Roopali, Maria Antonietta Mazzola, Radhika Raheja, Gopal Murugaiyan, Hasan Rajabi, Deepak Kumar, Thomas Pertel, Keren Regev, Russell Griffin, Lilian Aly, Pia Kivisakk, Parham Nejad, Bonny Patel, Nguendab Gwanyalla, Hillary Hei, Bonnie Glanz, Tanuja Chitnis, Howard L. Weiner, Roopali Gandhi

Abstract

Fingolimod (FTY720), the first oral treatment for multiple sclerosis (MS), blocks immune cell trafficking and prevents disease relapses by downregulation of sphingosine-1-phosphate receptor. We determined the effect of FTY720 on human T cell activation and effector function. T cells from MS patients and healthy controls were isolated to measure gene expression profiles in the presence or absence of FTY720 using nanostring and quantitative real-time polymerase chain reaction (qPCR). Cytokine protein expression was measured using luminex assay and flow cytometry analysis. Lentivirus vector carrying short hairpin RNA (shRNA) was used to knock down the expression of specific genes in CD4+ T cells. Chromatin immunoprecipitation was performed to assess T cell factor 1 (TCF-1) binding to promoter regions. Luciferase assays were performed to test the direct regulation of interferon gamma (IFN-γ) and granzyme B (GZMB) by TCF-1. Western blot analysis was used to assess the phosphorylation status of Akt and GSK3β. We showed that FTY720 treatment not only affects T cell trafficking but also T cell activation. Patients treated with FTY720 showed a significant reduction in circulating CD4 T cells. Activation of T cells in presence of FTY720 showed a less inflammatory phenotype with reduced production of IFN-γ and GZMB. This decreased effector phenotype of FTY720-treated T cells was dependent on the upregulation of TCF-1. FTY720-induced TCF-1 downregulated the pathogenic cytokines IFN-γ and GZMB by binding to their promoter/enhancer regions and mediating epigenetic modifications. Furthermore, we observed that TCF-1 expression was lower in T cells from multiple sclerosis patients than in those from healthy individuals, and FTY720 treatment increased TCF-1 expression in multiple sclerosis patients. These results reveal a previously unknown mechanism of the effect of FTY720 on human CD4+ T cell modulation in multiple sclerosis and demonstrate the role of TCF-1 in human T cell activation and effector function.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 3%
Unknown 31 97%

Demographic breakdown

Readers by professional status Count As %
Unspecified 6 19%
Researcher 5 16%
Student > Ph. D. Student 5 16%
Student > Master 4 13%
Student > Bachelor 4 13%
Other 8 25%
Readers by discipline Count As %
Unspecified 9 28%
Medicine and Dentistry 6 19%
Agricultural and Biological Sciences 5 16%
Immunology and Microbiology 5 16%
Neuroscience 3 9%
Other 4 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 April 2016.
All research outputs
#3,879,008
of 7,516,464 outputs
Outputs from Journal of Neuroinflammation
#539
of 972 outputs
Outputs of similar age
#160,767
of 308,653 outputs
Outputs of similar age from Journal of Neuroinflammation
#50
of 74 outputs
Altmetric has tracked 7,516,464 research outputs across all sources so far. This one is in the 27th percentile – i.e., 27% of other outputs scored the same or lower than it.
So far Altmetric has tracked 972 research outputs from this source. They receive a mean Attention Score of 4.6. This one is in the 32nd percentile – i.e., 32% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 308,653 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 36th percentile – i.e., 36% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 74 others from the same source and published within six weeks on either side of this one. This one is in the 28th percentile – i.e., 28% of its contemporaries scored the same or lower than it.