The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis.
The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis.
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DOI：
10.1101/gad.255331.114
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发表时间：
2015-02-15
影响因子：
10.5
通讯作者：
Murre C
中科院分区：
文献类型：
--
作者：
Miyazaki M;Miyazaki K;Chen S;Chandra V;Wagatsuma K;Agata Y;Rodewald HR;Saito R;Chang AN;Varki N;Kawamoto H;Murre C
Miyazaki等人的研究表明，Id2和Id3通过作用于Hif1a/Foxo/AKT/mTORC1通路上游以及c-myc/p19Arf模块，抑制先天变异型TFH细胞的发育和扩增。Id2和Id3表达缺失的小鼠发生结肠炎和αβ t细胞淋巴瘤，Id2和Id3表达缺失的淋巴瘤的转录特征显示与伯基特淋巴瘤相关的遗传缺陷相似。现在已经确定E和Id蛋白轴调节淋巴细胞发育的多个步骤。然而，尚不清楚E和Id蛋白如何机械地加强和维持naïve t细胞的命运。本研究表明，Id2和Id3抑制先天变异滤泡辅助T （TFH）细胞的发育和扩增。先天变异的TFH细胞需要主要组织相容性复合体（MHC） i类信号传导，并与生发中心B细胞相关。我们发现Id2和Id3诱导Foxo1和Foxp1表达拮抗TFH转录特征的激活。我们发现Id2和Id3作用于Hif1a/Foxo/AKT/mTORC1通路的上游，以及c-myc/p19Arf模块来控制细胞扩增。我们发现Id2和Id3表达缺失的小鼠发生结肠炎和αβ t细胞淋巴瘤。缺乏Id2和Id3表达的淋巴瘤显示c-myc水平升高，而p19Arf丰度下降。Id2-和id3缺失淋巴瘤的转录特征揭示了与伯基特淋巴瘤相关的遗传缺陷的相似性。我们提出，E-Id蛋白轴响应抗原受体和/或细胞因子信号，调节PI3K-AKT-mTORC1-Hif1a和c-myc/p19Arf通路的活性，以控制细胞扩张和稳态增殖。
Miyazaki et al. show that Id2 and Id3 suppress the development and expansion of innate variant TFH cells by acting upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module. Mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas, and the transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1–Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.
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