Developmental Stage-Dependent Collaboration Between the TNF Receptor-Associated Factor 6 and Lymphotoxin Pathways for B Cell Follicle Organization in Secondary Lymphoid Organs

J Immunol. 2007 Nov 15;179(10):6799-807. doi: 10.4049/jimmunol.179.10.6799.


Signal transduction pathways regulating NF-kappaB activation essential for microenvironment formation in secondary lymphoid organs remain to be determined. We investigated the effect of a deficiency of TNFR-associated factor 6 (TRAF6), which activates the classical NF-kappaB pathway, in splenic microenvironment formation. Two-week-old TRAF6-deficient mice showed severe defects in B cell follicle and marginal zone formation, similar to mutant mice defective in lymphotoxin (Lt) beta receptor (LtbetaR) signal induction of nonclassical NF-kappaB activation. However, analysis revealed a TRAF6 role in architecture formation distinct from its role in the early neonatal Lt signaling pathway. LtbetaR signal was essential for primary B cell cluster formation with initial differentiation of follicular dendritic cells (FDCs) in neonatal mice. In contrast, TRAF6 was dispensable for progression to this stage but was required for converting B cell clusters to B cell follicles and maintaining FDCs through to later stages. Fetal liver transfer experiments suggested that TRAF6 in radiation-resistant cells is responsible for follicle formation. Despite FDC-specific surface marker expression, FDCs in neonatal TRAF6-deficient mice had lost the capability to express CXCL13. These data suggest that developmentally regulated activation of TRAF6 in FDCs is required for inducing CXCL13 expression to maintain B cell follicles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / immunology
  • Cell Differentiation
  • Chemokine CXCL13 / biosynthesis
  • Chemokine CXCL13 / immunology*
  • Dendritic Cells, Follicular / immunology*
  • Dendritic Cells, Follicular / metabolism
  • Liver / growth & development
  • Liver / immunology
  • Liver / metabolism
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / immunology
  • Lymphotoxin beta Receptor / metabolism
  • Lymphotoxin-beta / biosynthesis
  • Lymphotoxin-beta / genetics
  • Lymphotoxin-beta / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Mutant Strains
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Spleen / growth & development
  • Spleen / immunology*
  • Spleen / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology*
  • TNF Receptor-Associated Factor 6 / metabolism


  • Antigens, Differentiation
  • Chemokine CXCL13
  • Cxcl13 protein, mouse
  • Ltb protein, mouse
  • Lymphotoxin beta Receptor
  • Lymphotoxin-beta
  • NF-kappa B
  • TNF Receptor-Associated Factor 6