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FoxA1 in synergy with IFNβ controls PDL1 expression in anti-inflammatory T cells via binding to a 60-nucleotide region in the Pdl1 promoter
Author(s): ,
M. Hadi
Affiliations:
Neuroinflammation Unit, Biotech Research & Innovation Centre (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen Biocentre, Copenhagen, Denmark
,
L. Munk Rasmussen
Affiliations:
Neuroinflammation Unit, Biotech Research & Innovation Centre (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen Biocentre, Copenhagen, Denmark
,
M. Kosicki
Affiliations:
Neuroinflammation Unit, Biotech Research & Innovation Centre (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen Biocentre, Copenhagen, Denmark
,
R. Carlsson
Affiliations:
Neuroinflammation Unit, Biotech Research & Innovation Centre (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen Biocentre, Copenhagen, Denmark
S. Issazadeh-Navikas
Affiliations:
Neuroinflammation Unit, Biotech Research & Innovation Centre (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen Biocentre, Copenhagen, Denmark
ECTRIMS Online Library. Hadi M. Oct 12, 2018; 228919
Mahdieh Hadi
Mahdieh Hadi
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Abstract: P1078

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Immunology

Multiple sclerosis (MS) is a neuroinflammatory disease, which progression depends on autoreactive T cells. Regulatory T (Tregs) cells, particularly FoxA1+Tregs have protective role in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). IFNβ is inducing the transcription factor FoxA1 in T cells and FoxA1+ Tregs anti-inflammatory functions are mediated by expression of the immunomodulatory molecule programmed death-ligand 1 (PDL1), which binds to PD-1 on activated T cells, therefore it is central to understand how FoxA1, the fate determining transcription factor, and IFNβ are regulating Pdl1 gene. To find the mechanism behind this regulation we have used different methods like reporter assay, flow cytometry and immunofluorescent staining.
Here, we have shown that FoxA1 is sufficient to activate the Pdl1 promoter. We report that FoxA1 upregulates the expression of PDL1 in T cells by direct binding to B region in the Pdl1 promoter (Pdl1-B). Although FoxA1 is sufficient to activate the Pdl1 promoter in primary T cells, IFNβ treatment in luciferase reporter assays shows some synergistic effect with FoxA1 too. We narrowed down FoxA1's binding site to a 27 nt site in the Pdl1-B promoter, then we have shown that synergistic activation of the promoter by FoxA1 and IFNβ was mediated via activation of STAT1/2/3 which bind a slightly larger region, stretching to 60 nt spanning the FoxA1 binding site. This 60 nt region is necessary and sufficient for PDL1 response to FoxA1 and IFNβ. In addition, it is shown that in the absence of STAT1/2/3, the FoxA1 effect on Pdl1 promoter has not abrogated, suggesting that FoxA1 is the main mediator in inducing PDL1 expression by IFNβ.
In conclusion, we have identified a minimal Pdl1 promoter region sufficient to recover the full Pdl1 promoter activity, and therefore could pave the way toward a new potential target to regulate the T-cell PD-L1 expression and secure anti-inflammatory capacity of FoxA1+Treg cells.
Disclosure: Hereby, we confirm that we had no conflict of interest regarding the results presented here. We have fundings from McDonald fellowship (MSIF) to support the project. In addition, we had additional fundings for this project from other organisation, they are The Lundbeck Foundation and Danish council for independent research (Det frie forskningsråd).

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