IQGAP1 restrains T-cell cosignaling mediated by OX40

Yuko Okuyama, Hiroyuki Nagashima, Masuko Ushio-Fukai, Michael Croft, Naoto Ishii, Takanori So

研究成果: Article査読

6 被引用数 (Scopus)

抄録

A costimulatory signal from the tumor necrosis factor receptor (TNFR) family molecule OX40 (CD134), which is induced on activated T cells, is important for T-cell immunity. Aberrant OX40 cosignaling has been implicated in autoimmune and inflammatory disorders. However, the molecular mechanism by which the OX40 cosignaling regulates the T-cell response remains obscure. We found that OX40 associated with a scaffold protein, IQ motif-containing GTPase-activating protein 1 (IQGAP1) after ligation by its ligand OX40L. Naïve CD4+ T cells from Iqgap1−/− mice displayed enhanced proliferation and cytokine secretion upon receiving OX40 cosignaling. A C-terminal IQGAP1 region was responsible for its association with OX40, and TNFR-associated factor 2 (TRAF2) bridged these two proteins. The enhanced cytokine response in Iqgap1−/− T cells was restored by the expression of the C-terminal IQGAP1. Thus, the IQGAP1 binding limits the OX40 cosignaling. Disease severity of experimental autoimmune encephalomyelitis (EAE) was significantly exacerbated in Iqgap1−/− mice as compared to wild-type mice. Additionally, recipient mice with Iqgap1−/− donor CD4+ T cells exhibited significantly higher EAE scores than those with their wild-type counterparts, and OX40 blockade led to a significant reduction in the EAE severity. Thus, our study defines an important component of the OX40 cosignaling that restricts inflammation driven by antigen-activated T cells.

本文言語English
ページ(範囲)540-554
ページ数15
ジャーナルFASEB Journal
34
1
DOI
出版ステータスPublished - 2020 1月 1

ASJC Scopus subject areas

  • バイオテクノロジー
  • 生化学
  • 分子生物学
  • 遺伝学

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