TNFR-associated factors 2 and 5 differentially regulate the instructive IL-6 receptor signaling required for Th17 development

IL-17-producing CD4⁺ T cells (Th17 cells) regulate host defense and immune pathogenesis, and IL-6 plays an important role for the differentiation of Th17 cells. We have previously identified that TNFR-associated factor (TRAF)5 binds to the signaltransducing receptor gp130 through the C-terminal TRAF domain and inhibits Th17 development mediated by IL-6. Although gp130 has TRAF-binding motifs that can be recognized by other TRAF family proteins, it is unclear how TRAFs regulate IL-6-driven Th17 differentiation in general. Using retrovirus-mediated gene complementation and gene silencing approaches, we found that not only TRAF5 but also TRAF2 restrained the IL-6R signaling, whereas TRAF1, TRAF3, TRAF4, and TRAF6 did not. Traf2 silencing further promoted the ability of naive CD4⁺ T cells from Traf5^-/- mice to differentiate into Th17 cells. Notably, TRAF5 but not TRAF2 expressed in naive CD4⁺ T cells was rapidly downregulated after TCR triggering, which indicates that TRAF5 specifically inhibits instructive IL-6 signals in the initial stage of Th17 development. Collectively, our results demonstrate a dedicated role for TRAF2 and TRAF5 in the process of IL-6-mediated Th17 development and a differential role for TCR signaling in regulation of TRAF2 and TRAF5. Therefore, both TRAF2 and TRAF5 work as important regulators of the IL-6R signaling needed for Th17 development.