Abstract
T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / immunology*
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Cell Lineage
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Electrophoretic Mobility Shift Assay
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Female
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Interleukin-17 / immunology
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Interleukin-17 / metabolism*
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Mice
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Mice, Mutant Strains
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Cytoplasmic and Nuclear / immunology*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Retinoic Acid / immunology*
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Receptors, Retinoic Acid / metabolism
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Receptors, Thyroid Hormone / immunology*
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Receptors, Thyroid Hormone / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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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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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
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Trans-Activators / immunology*
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Trans-Activators / metabolism
Substances
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Rorc protein, mouse
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Trans-Activators