TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells

Immunity. 2004 Nov;21(5):629-42. doi: 10.1016/j.immuni.2004.09.011.


To examine the role of the TNF-R superfamily signaling protein TRAF2 in mature B cell development and NF-kappaB activation, conditionally TRAF2-deficient mice were produced. B cells lacking TRAF2 expression in these mice possessed a selective survival advantage, accumulated in the lymph nodes and splenic marginal zone, were larger in size, and expressed increased levels of CD21/35. These TRAF2-deficient B cells could not proliferate or activate the canonical NF-kappaB pathway in response to CD40 ligation. By contrast, noncanonical NF-kappaB activation was constitutively hyperactive, with TRAF2-deficient B cells exhibiting close to maximal processing of NF-kappaB2 from p100 to p52 and high levels of constitutive p52 and RelB DNA binding activity. These findings establish TRAF2 as a multifunctional regulator of NF-kappaB activation that mediates activation of the canonical pathway but acts as a negative regulator of the noncanonical pathway. This dual functionality explains the contrasting roles of TRAF2 in B cell maturation and activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • CD40 Antigens / physiology
  • DNA / metabolism
  • Immunophenotyping
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-rel / analysis
  • TNF Receptor-Associated Factor 2 / physiology*
  • TNF Receptor-Associated Factor 3 / metabolism
  • Transcription Factor RelB
  • Transcription Factors / metabolism


  • CD40 Antigens
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-rel
  • Relb protein, mouse
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Transcription Factors
  • Transcription Factor RelB
  • DNA