Abstract
T helper 17 (Th17) cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 cell differentiation is relatively unknown. We demonstrate that CD4(+) T cells lacking Itk, a tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or constitutively activated nuclear factor of activated T cells (NFAT). Conversely, decreased TCR stimulation or calcineurin inhibition preferentially reduced IL-17A expression. We further found that the promoter of Il17a but not Il17f has a conserved NFAT binding site that bound NFATc1 in wild-type but not Itk-deficient cells, even though both exhibited open chromatin conformations. Finally, Itk(-/-) mice also showed differential regulation of IL-17A and IL-17F in vivo. Our results suggest that Itk specifically couples TCR signaling to Il17a expression and the differential regulation of Th17 cell cytokines through NFATc1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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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Calcium / immunology
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Calcium / metabolism
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Cytokines / immunology*
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Cytokines / metabolism
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Interleukin-17 / biosynthesis*
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Lung / immunology
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Lung / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NFATC Transcription Factors / immunology
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NFATC Transcription Factors / metabolism
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Phospholipase C gamma / immunology
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Phospholipase C gamma / metabolism
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Promoter Regions, Genetic / immunology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / 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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Signal Transduction / immunology
Substances
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Cytokines
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Interleukin-17
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RORC protein, human
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Receptors, Antigen, T-Cell
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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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Protein-Tyrosine Kinases
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emt protein-tyrosine kinase
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Protein Serine-Threonine Kinases
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Phospholipase C gamma
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Calcium