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

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

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Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
1] Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan. [2] Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
Division of Immune Regulation, La Jolla Institute, La Jolla, California, USA.


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.

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