title: TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development.
abstract: 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 signal-transducing 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.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagashima
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okuyama
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan tso@med.tohoku.ac.jp.
authors.forename: Takanori
authors.identifier: 0000-0003-3004-8526
authors.initials: T
authors.lastname: So
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D050822:Cytokine Receptor gp130