Abstract
Regulatory T (T reg) cells are central mediators of immune suppression. As such, T reg cells are characterized by a distinct pattern of gene expression, which includes up-regulation of immunosuppressive genes and silencing of inflammatory cytokine genes. Although an increasing number of transcription factors that regulate T reg cells have been identified, the mechanisms by which the T reg cell-specific transcriptional program is maintained and executed remain largely unknown. The Nr4a family of nuclear orphan receptors, which we recently identified as essential for the development of T reg cells, is highly expressed in mature T reg cells as well, suggesting that Nr4a factors play important roles even beyond T reg cell development. Here, we showed that deletion of Nr4a genes specifically in T reg cells caused fatal systemic immunopathology. Nr4a-deficient T reg cells exhibited global alteration of the expression of genes which specify the T reg cell lineage, including reduction of Foxp3 and Ikzf4. Furthermore, Nr4a deficiency abrogated T reg cell suppressive activities and accelerated conversion to cells with Th2 and follicular helper T (Tfh) effector-like characteristics, with heightened expression of Th2 and Tfh cytokine genes. These findings demonstrate that Nr4a factors play crucial roles in mature T reg cells by directly controlling a genetic program indispensable for T reg cell maintenance and function.
© 2015 Sekiya et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / immunology
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / immunology
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
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Receptors, Steroid / genetics
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Receptors, Steroid / immunology*
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Receptors, Steroid / metabolism
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / immunology
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Receptors, Thyroid Hormone / metabolism
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Regulatory / immunology*
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Th2 Cells / immunology
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Transcription, Genetic
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Nerve Tissue Proteins
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Nr4a1 protein, mouse
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Nr4a2 protein, mouse
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Nr4a3 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Zfpn1a4 protein, mouse
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Interleukin-4