IQGAP1 restrains T-cell cosignaling mediated by OX40

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)540-554
Number of pages15
JournalFASEB Journal
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • CD4 T cells
  • T-cell inflammation
  • TNFRSF
  • autoimmunity
  • cosignaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'IQGAP1 restrains T-cell cosignaling mediated by OX40'. Together they form a unique fingerprint.

  • Cite this

    Okuyama, Y., Nagashima, H., Ushio-Fukai, M., Croft, M., Ishii, N., & So, T. (2020). IQGAP1 restrains T-cell cosignaling mediated by OX40. FASEB Journal, 34(1), 540-554. https://doi.org/10.1096/fj.201900879RR