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

Hiroyuki Nagashima; Yuko Okuyama; Atsuko Asao; Takeshi Kawabe; Satoshi Yamaki; Hiroyasu Nakano; Michael Croft; Naoto Ishii; Takanori So

doi:10.1038/ni.2863

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

Hiroyuki Nagashima, Yuko Okuyama, Atsuko Asao, Takeshi Kawabe, Satoshi Yamaki, Hiroyasu Nakano, Michael Croft, Naoto Ishii, Takanori So^*

^*Corresponding author for this work

Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	449-456
Number of pages	8
Journal	Nature Immunology
Volume	15
Issue number	5
DOIs	https://doi.org/10.1038/ni.2863
State	Published - 2014/05

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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

abstract = "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.",

author = "Hiroyuki Nagashima and Yuko Okuyama and Atsuko Asao and Takeshi Kawabe and Satoshi Yamaki and Hiroyasu Nakano and Michael Croft and Naoto Ishii and Takanori So",

note = "Funding Information: We thank W. Heath (University of Melbourne) for OT-II mice; S. Nagata (Kyoto University) and S. Akira (Osaka University) for the Flag-pEF-STAT3 vector. Supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (C) (24590571 to T.S.), the Ichiro Kanehara Foundation (T.S.), the Takeda Science Foundation (T.S.), the Suzuken Memorial Foundation (T.S.) and the US National Institutes of Health (AI049453 to M.C.).",

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doi = "10.1038/ni.2863",

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T1 - The adaptor TRAF5 limits the differentiation of inflammatory CD4 + T cells by antagonizing signaling via the receptor for IL-6

AU - Nagashima, Hiroyuki

AU - Okuyama, Yuko

AU - Asao, Atsuko

AU - Kawabe, Takeshi

AU - Yamaki, Satoshi

AU - Nakano, Hiroyasu

AU - Croft, Michael

AU - Ishii, Naoto

AU - So, Takanori

N1 - Funding Information: We thank W. Heath (University of Melbourne) for OT-II mice; S. Nagata (Kyoto University) and S. Akira (Osaka University) for the Flag-pEF-STAT3 vector. Supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (C) (24590571 to T.S.), the Ichiro Kanehara Foundation (T.S.), the Takeda Science Foundation (T.S.), the Suzuken Memorial Foundation (T.S.) and the US National Institutes of Health (AI049453 to M.C.).

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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.

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

Abstract

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