| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Outline of Final Research Achievements |
We investigated the phenotype of Tfh cells in patients with SLE and epigenetic modifications by STAT family transcription factors. The proportion of CD4+CXCR5+CXCR3+CCR6-CD69+ Tfh-Th1-like cells was increased in SLE patients. In vitro, IL-12 increased differentiation of CD4+CXCR5+CXCR3+Bcl-6+T-bet+IL-21+IFN-γ+ Tfh-Th1-like cells through phosphorylation of STAT1 and STAT4. The loci of Bcl-6 and T-bet at STAT binding sites in TCR-stimulated CD4+ T cells were marked by bivalent histone modifications. After IL-12 stimulation, both STAT1 and STAT4 directly bound on Bcl-6 and T-bet gene loci accompanied by suppression of trimethylated H3K27me3 repressive histone mark. Knockdown of STAT1 or STAT4 abolished the capacity of CD4+ T cells to differentiate into Tfh-Th1-like cells after IL-12 stimulation. Our observations suggest that IL-12-mediated activation of both STAT1 and STAT4 alters histone modification and may commit the characteristic expansion of Tfh-Th1-like cells in SLE.
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