Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12827-32. doi: 10.1073/pnas.1105774108. Epub 2011 Jul 18.

Abstract

Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-κB-inducing kinase (NIK), a central component of the noncanonical NF-κB signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-κB. Our findings suggest that the noncanonical NF-κB pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.

Publication types

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

MeSH terms

  • Animals
  • B-Cell Activation Factor Receptor / genetics
  • B-Cell Activation Factor Receptor / immunology
  • B-Cell Activation Factor Receptor / metabolism
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Female
  • Flow Cytometry
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Immunization / methods
  • Inducible T-Cell Co-Stimulator Ligand
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • NF-kappaB-Inducing Kinase
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / immunology*
  • Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism

Substances

  • B-Cell Activation Factor Receptor
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Lipopolysaccharides
  • NF-kappa B
  • Proteins
  • Tnfrsf13c protein, mouse
  • Protein Serine-Threonine Kinases
  • Leukocyte Common Antigens