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.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Line
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Forkhead Box Protein O1
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Forkhead Transcription Factors / deficiency
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Humans
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Immunophenotyping
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Lymphocyte Count
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Mice
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Mice, Knockout
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Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors
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Nuclear Receptor Subfamily 1, Group F, Member 3 / chemistry
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
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Phenotype
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic
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Protein Interaction Domains and Motifs
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Th17 Cells / cytology
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Th17 Cells / immunology
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Th17 Cells / metabolism*
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Transcription, Genetic
Substances
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt