| First Author | Okuyama Y | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 1 | Pages | 540-554 |
| PubMed ID | 31914585 | Mgi Jnum | J:299955 |
| Mgi Id | MGI:6491741 | Doi | 10.1096/fj.201900879RR |
| Citation | Okuyama Y, et al. (2020) IQGAP1 restrains T-cell cosignaling mediated by OX40. FASEB J 34(1):540-554 |
| abstractText | 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. Naive 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. |
