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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Differentiation / immunology
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Cell Differentiation / physiology*
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Cell Line
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Forkhead Box Protein O3 / immunology
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Forkhead Box Protein O3 / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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HEK293 Cells
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Humans
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-1 / immunology
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Interleukin-1 / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism*
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Th1 Cells / immunology
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Th1 Cells / metabolism*
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Th1 Cells / pathology*
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Transcription Factors / metabolism*
Substances
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Eomes protein, mouse
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Forkhead Box Protein O3
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FoxO3 protein, mouse
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Interleukin-1
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Receptors, Antigen, T-Cell
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T-Box Domain Proteins
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Transcription Factors
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor