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J Immunol. 2015 Aug 15;195(4):1791-803. doi: 10.4049/jimmunol.1500849. Epub 2015 Jul 13.

Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.

Author information

1
INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
2
INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France celine.charvet@inserm.fr.

Abstract

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.

PMID:
26170390
DOI:
10.4049/jimmunol.1500849
[Indexed for MEDLINE]
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