Foxo1 is a T cell–intrinsic inhibitor of the RORγt-Th17 program

A Lainé, B Martin, M Luka, L Mir, C Auffray… - The Journal of …, 2015 - journals.aai.org
A Lainé, B Martin, M Luka, L Mir, C Auffray, B Lucas, G Bismuth, C Charvet
The Journal of Immunology, 2015journals.aai.org
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 …
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.
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