| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Outline of Final Research Achievements |
We previously reported that γc-cytokines, especially IL-15, play a critical role in determining whether or not CD8 cells exert cytotoxic activity in an experimental GVHD mouse model. We then hypothesized that cooperation between γc-cytokine and TCR/co-stimulation signaling is critical in enabling the transition of naive CD8 T cells into effector cells. In this study, we demonstrated that the transcription factor interferon regulatory factor 8 (IRF8) is persistently activated by these two signals in CD8 T cells. Blocking these signaling pathways by either a ZAP70 inhibitor or a Jak3 inhibitor abrogated IRF8 upregulation and inhibited effector differentiation in CD8 T cells. In an experimental GVHD mouse model, IRF8 deficient CD8 T cells failed to differentiate into cytotoxic T cells, causing reduced pathology. Together, our work shows that IRF8 integrates the TCR/co-stimulation and γc-cytokine signaling pathways and drives transition of naive CD8 T cells to effector cells.
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