Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells
Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells
复制标题
DOI：
10.4049/jimmunol.1801083
复制
发表时间：
2019-02
期刊：
影响因子：
--
通讯作者：
Takeshi Yamada;Shogo Nabe;Koji Toriyama;Junpei Suzuki;Kazuki Inoue;Yuuki Imai;A. Shiraishi;K. Takenaka;M. Yasukawa;M. Yamashita
中科院分区：
文献类型：
--
作者：
Takeshi Yamada;Shogo Nabe;Koji Toriyama;Junpei Suzuki;Kazuki Inoue;Yuuki Imai;A. Shiraishi;K. Takenaka;M. Yasukawa;M. Yamashita
虽然组蛋白H3 K27的甲基化状态在CD 4 + T细胞分化及其功能中起着关键作用，但Utx组蛋白H3 K27去甲基化酶在CD 8 + T细胞依赖性免疫应答中的作用仍不清楚。因此，我们产生了T细胞特异性Utxflox/flox Cd 4-Cre Tg（Utx KO）小鼠以确定Utx在CD 8 + T细胞中的作用。用表达OVA的单核细胞增生李斯特菌感染野生型（WT）和Utx KO小鼠，以分析Ag特异性CD 8 + T细胞的免疫应答。WT和Utx KO小鼠之间初次感染后Ag特异性CD 8 + T细胞的数量没有显著差异。然而，Utx缺陷导致更多的Ag特异性CD 8 + T细胞后，二次感染。与WT相比，Utx KO CD 8 + T细胞的连续转移导致初级应答中更多数量的记忆细胞。我们观察到在Utx KO CD 8 + T细胞中效应相关转录因子（包括编码Blimp 1的Prdm 1）的基因表达降低。我们证实，Utx KO细胞中Prdm 1基因位点组蛋白H3 K27的三甲基化水平高于WT细胞。用Utx-辅因子α-酮戊二酸处理CD 8 + T细胞阻碍了记忆的形成，而Utx抑制剂GSK-J 4增强了WT CD 8 + T细胞的记忆形成。这些数据表明Utx通过表观遗传学调节基因表达来负控制Ag刺激的CD 8 + T细胞的记忆形成。基于这些发现，我们确定了Utx与银刺激的CD 8 + T细胞分化之间的关键联系。
Although the methylation status of histone H3K27 plays a critical role in CD4+ T cell differentiation and its function, the role of Utx histone H3K27 demethylase in the CD8+ T cell–dependent immune response remains unclear. We therefore generated T cell–specific Utxflox/flox Cd4-Cre Tg (Utx KO) mice to determine the role of Utx in CD8+ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells. There was no significant difference in the number of Ag-specific CD8+ T cells upon primary infection between WT and Utx KO mice. However, Utx deficiency resulted in more Ag-specific CD8+ T cells upon secondary infection. Adoptive transfer of Utx KO CD8+ T cells resulted in a larger number of memory cells in the primary response than in WT. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8+ T cells. We confirmed that the trimethylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8+ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, whereas Utx inhibitor GSK-J4 enhanced the memory formation in WT CD8+ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells by epigenetically regulating the gene expression. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8+ T cells.