| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Outline of Final Research Achievements |
We have discovered that OX40 associated with a scaffold protein IQGAP1 after ligation by OX40L expressed on antigen-presenting cells. The C-terminal domain of IQGAP1 (IQGAP1-C) was required for its association with OX40, and TRAF2 augmented the binding between OX40 and IQGAP1-C. Naive CD4+ T cells from Iqgap1-/- mice displayed an enhanced ability to produce effector cytokines in response to antigen and OX40L. Retroviral transduction of IQGAP1-C into Iqgap1-/- T cells rescued these enhanced responses, suggesting that IQGAP1 limits the process of OX40-dependent T cell activation. Sublethally irradiated recipient mice that received adoptively transferred Iqgap1-/- CD4+ T cells and were immunized with MOG peptide had significantly higher EAE clinical scores than those recipient mice with wild-type CD4+ T cells. These results demonstrate that IQGAP1 is a component of the OX40 signalosome and limits cosignaling that promotes T cell activation and autoimmune disease development.
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