PDCD5 regulates iNKT cell terminal maturation and iNKT1 fate decision
PDCD5 regulates iNKT cell terminal maturation and iNKT1 fate decision
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PDCD5 调节 iNKT 细胞终末成熟和 iNKT1 命运决定。
DOI：
10.1038/s41423-018-0059-2
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发表时间：
2019
影响因子：
24.1
通讯作者：
Ge Qing
中科院分区：
文献类型：
--
作者：
Wang Ke;Zhang Xinwei;Wang Yifan;Jin Gaowen;Li Mingyang;Zhang Shusong;Hao Jie;Jin Rong;Huang Xiaojun;Wu Hounan;Zhang Jun;Chen Yingyu;Ge Qing
不变性自然杀伤T1（invariant natural killer T1，iNKT 1）细胞具有优先表达T-box转录因子T-bet（由Tbx 21编码）和产生细胞因子IFN-γ的特征，但其发育过程与胸腺中iNKT 1谱系多样性之间的关系尚不清楚。在本研究中，我们报告了程序性细胞死亡5（PDCD 5）在iNKT细胞终末成熟和iNKT 1命运决定中的关键作用。T细胞特异性PDCD 5缺失的小鼠胸腺和外周iNKT细胞数量减少，主要表现为不成熟表型，对α-半乳糖神经酰胺的反应存在缺陷。PDCD 5的缺失还通过在早期胸腺发育阶段（在CD 44上调之前）降低iNKT细胞中的T-bet表达来选择性地消除iNKT 1谱系。我们进一步证明，TOX 2，在第1阶段在iNKT细胞中高度表达的高迁移率族蛋白之一，可以通过PDCD 5稳定，促进Tbx 21启动子区域中允许的组蛋白H3 K4 me 3修饰。这些数据表明PDCD 5/TOX 2在iNKT 1谱系确定中的关键和独特作用。他们还表明iNKT 1的命运可能在胸腺中iNKT细胞的发育阶段被编程。
Invariant natural killer T1 (iNKT1) cells are characterized by the preferential expression of T-box transcription factor T-bet (encoded byTbx21) and the production of cytokine IFN-γ, but the relationship between the developmental process and iNKT1 lineage diversification in the thymus remains elusive. We report in the present study a crucial role of programmed cell death 5 (PDCD5) in iNKT cell terminal maturation and iNKT1 fate determination. Mice with T cell-specific deletion of PDCD5 had decreased numbers of thymic and peripheral iNKT cells with a predominantly immature phenotype and defects in response to α-galactosylceramide. Loss of PDCD5 also selectively abolished the iNKT1 lineage by reducing T-bet expression in iNKT cells at an early thymic developmental stage (before CD44 upregulation). We further demonstrated that TOX2, one of the high mobility group proteins that was highly expressed in iNKT cells at stage 1 and could be stabilized by PDCD5, promoted the permissive histone H3K4me3 modification in the promoter region ofTbx21. These data indicate a pivotal and unique role of PDCD5/TOX2 in iNKT1 lineage determination. They also suggest that the fate of iNKT1 may be programmed at the developmental stage of iNKT cells in the thymus.