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

Adaptors of the TRAF family are tumor-necrosis factor receptor–associated factors. So and colleagues show that TRAF5 negative regulates the IL-6 receptor signaling pathway, which limits the induction of proinflammatory CD4 + T cells. 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 T H 17 subset of helper T cells. Accordingly, T H 17 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.