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Immunity. 2016 Oct 18;45(4):774-787. doi: 10.1016/j.immuni.2016.09.010. Epub 2016 Oct 11.

Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes.

Author information

1
UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
2
UGM 4127, Oncopole, Toulouse 31059, France.
3
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse 31024, France.
4
Molecular Biology Section, Division of Biological Sciences and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0377, USA.
5
UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France. Electronic address: anne.dejean@inserm.fr.

Abstract

The transcription factor Foxo3 plays a crucial role in myeloid cell function but its role in lymphoid cells remains poorly defined. Here, we have shown that Foxo3 expression was increased after T cell receptor engagement and played a specific role in the polarization of CD4+ T cells toward pathogenic T helper 1 (Th1) cells producing interferon-γ (IFN-γ) and granulocyte monocyte colony stimulating factor (GM-CSF). Consequently, Foxo3-deficient mice exhibited reduced susceptibility to experimental autoimmune encephalomyelitis. At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN-γ and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.

KEYWORDS:

CD4 T cell differentiation; EAE; Eomes; GM-CSF; IFN-γ; T-bet; autoimmunity; pathogenic Th1; transcription factors

PMID:
27742544
PMCID:
PMC5141513
DOI:
10.1016/j.immuni.2016.09.010
[Indexed for MEDLINE]
Free PMC Article

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