The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6

Nat Immunol. 2014 May;15(5):449-56. doi: 10.1038/ni.2863. Epub 2014 Mar 30.


The physiological functions of members of the tumor-necrosis factor (TNF) receptor (TNFR)-associated factor (TRAF) family in T cell immunity are not well understood. We found that in the presence of interleukin 6 (IL-6), naive TRAF5-deficient CD4(+) T cells showed an enhanced ability to differentiate into the TH17 subset of helper T cells. Accordingly, TH17 cell-associated experimental autoimmune encephalomyelitis (EAE) was greatly exaggerated in Traf5(-/-) mice. Although it is normally linked with TNFR signaling pathways, TRAF5 constitutively associated with a cytoplasmic region in the signal-transducing receptor gp130 that overlaps with the binding site for the transcription activator STAT3 and suppressed the recruitment and activation of STAT3 in response to IL-6. Our results identify TRAF5 as a negative regulator of the IL-6 receptor signaling pathway that limits the induction of proinflammatory CD4(+) T cells that require IL-6 for their development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cytokine Receptor gp130 / metabolism*
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Interleukin-6 / immunology
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • T-Lymphocyte Subsets / immunology*
  • TNF Receptor-Associated Factor 5 / genetics
  • TNF Receptor-Associated Factor 5 / metabolism*
  • Th17 Cells / immunology*
  • Transcriptional Activation / genetics


  • CD4 Antigens
  • Interleukin-6
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • STAT3 Transcription Factor
  • TNF Receptor-Associated Factor 5
  • myelin oligodendrocyte glycoprotein (34-56)
  • Cytokine Receptor gp130