Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK

Blood. 2009 Jun 25;113(26):6603-10. doi: 10.1182/blood-2008-12-192914. Epub 2009 May 1.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Encephalomyelitis, Autoimmune, Experimental / enzymology*
  • Encephalomyelitis, Autoimmune, Experimental / etiology
  • Enzyme Activation
  • Gene Expression Regulation, Developmental
  • Glycoproteins / immunology
  • Interleukin-6 / physiology
  • Mice
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein
  • NF-kappaB-Inducing Kinase
  • Peptide Fragments / immunology
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Interleukin-6 / physiology
  • STAT3 Transcription Factor / physiology
  • Signal Transduction / physiology
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / enzymology

Substances

  • DNA-Binding Proteins
  • Glycoproteins
  • Interleukin-6
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Rag2 protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Protein Serine-Threonine Kinases