强直性LAT-HDAC7信号维持Nur77和Irf4表达以调节初始CD4 T细胞。
Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.
作者信息
Myers Darienne R, Lau Tannia, Markegard Evan, Lim Hyung W, Kasler Herbert, Zhu Minghua, Barczak Andrea, Huizar John P, Zikherman Julie, Erle David J, Zhang Weiguo, Verdin Eric, Roose Jeroen P
机构信息
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
出版信息
Cell Rep. 2017 May 23;19(8):1558-1571. doi: 10.1016/j.celrep.2017.04.076.
CD4 T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4 T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (T2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4 T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4 T cell proliferation and uncover a suppressive role for Irf4 in T2 polarization; halving Irf4 gene-dosage leads to increases in GATA3 and IL-4 cells. Our studies reveal that naive CD4 T cells are dynamically tuned by tonic LAT-HDAC7 signals.
CD4 T细胞以前馈方式分化为辅助性T细胞亚群，这些前馈方式依赖于来自T细胞受体（TCR）、细胞因子和谱系特异性转录因子的协同信号。初始CD4 T细胞避免前馈机制的自发激活，但保持一种准备就绪的状态。缺乏衔接分子LAT的T细胞表现出TCR诱导信号受损，但在小鼠中会引发自发性淋巴细胞增殖性辅助性T 2（T2）细胞综合征。因此，LAT构成了一个无法解释的维持线索。在这里，我们证明，通过LAT的张力信号持续地将阻遏物HDAC7从CD4 T细胞的细胞核中输出。没有这种张力信号，HDAC7的靶基因Nur77和Irf4会受到抑制。我们发现Nur77抑制CD4 T细胞增殖，并揭示了Irf4在T2极化中的抑制作用；将Irf4基因剂量减半会导致GATA3和IL-4细胞增加。我们的研究表明，初始CD4 T细胞由张力性LAT-HDAC7信号动态调节。
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