Abstract
Th17 cells play an important role in mediating autoimmune diseases, but the molecular mechanism underlying Th17 differentiation is incompletely understood. We show here that NF-kappaB-inducing kinase (NIK), which is known to regulate B-cell maturation and lymphoid organogenesis, is important for the induction of Th17 cells. NIK-deficient naive CD4 T cells are attenuated in the differentiation to Th17 cells, although they are competent in committing to the other effector lineages. Consistently, NIK knockout mice are resistant to experimental autoimmune encephalomyelitis, a disease model that involves the function of Th17 cells. This phenotype was also detected in Rag2 knockout mice reconstituted with NIK-deficient T cells, confirming a T-cell intrinsic defect. We further show that NIK mediates synergistic activation of STAT3 by T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates activation of STAT3 and induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and experimental autoimmune encephalitis induction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Animals
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CD4-Positive T-Lymphocytes / cytology*
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CD4-Positive T-Lymphocytes / immunology
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Cell Differentiation
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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Encephalomyelitis, Autoimmune, Experimental / enzymology*
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Encephalomyelitis, Autoimmune, Experimental / etiology
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Enzyme Activation
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Gene Expression Regulation, Developmental
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Glycoproteins / immunology
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Interleukin-6 / physiology
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Mice
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein
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NF-kappaB-Inducing Kinase
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Peptide Fragments / immunology
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Interleukin-6 / physiology
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STAT3 Transcription Factor / physiology
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Signal Transduction / physiology
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / enzymology
Substances
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DNA-Binding Proteins
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Glycoproteins
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Interleukin-6
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Rag2 protein, mouse
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Receptors, Antigen, T-Cell
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Receptors, Interleukin-6
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STAT3 Transcription Factor
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Stat3 protein, mouse
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myelin oligodendrocyte glycoprotein (35-55)
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Protein Serine-Threonine Kinases