YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells.
YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells.
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DOI：
10.1016/j.isci.2018.03.009
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发表时间：
2018-04-27
期刊：
影响因子：
5.8
通讯作者：
Junghans RP
中科院分区：
文献类型：
--
作者：
Balkhi MY;Wittmann G;Xiong F;Junghans RP
T细胞在慢性感染和恶性肿瘤中浸润受影响的器官，但它们可能由于耗尽而无法根除病毒感染的细胞或肿瘤。这份报告描述了一个阴阳-1（YY 1）为中心的机制，与疲惫相关的各种组件。利用慢性T细胞活化的体外重建，YY 1显示出正调节检查点受体PD 1、Lag 3和Tim 3，并负调节I型细胞因子白细胞介素-2（IL-2）（与Ezh 2组蛋白甲基转移酶协作）和干扰素γ（IFN-γ）。其他测试表明，IL-2失败驱动细胞毒性功能下降的一个大部分，而不仅仅是检查点受体-配体相互作用，这是目前抗衰竭疗法的焦点。临床评估证实，在HIV患者的黑色素瘤浸润淋巴细胞和PD 1 + T细胞中，YY 1和Ezh 2升高。耗竭是一个主动的过程，是通过CD 3/CD 28 → p38 MAPK/JNK→ YY 1 →耗竭的反馈回路中重复的双信号刺激的顶点。转录因子YY 1被证明是T细胞耗竭的主要调节因子YY 1募集Ezh 2组蛋白甲基转移酶以共同抑制IL-2细胞因子产生通过p38 MAPK/JNK途径的持续信号1+2刺激促进YY 1转录体内黑色素瘤和HIV耗竭的PD 1 + T细胞被证实升高YY 1和Ezh 2癌症系统生物学;免疫应答;免疫系统病症
T cells infiltrate affected organs in chronic infections and malignancy, but they may fail to eradicate virus-infected cells or tumor because of exhaustion. This report describes a Yin Yang-1 (YY1)-centered mechanism for diverse components that have been correlated with exhaustion. Utilizing an in vitro reconstruction of chronic T cell activation, YY1 is shown to positively regulate the checkpoint receptors PD1, Lag3, and Tim3 and to negatively regulate the type I cytokines interleukin-2 (IL-2) (in collaboration with Ezh2 histone methyltransferase) and interferon gamma (IFN-γ). Other tests suggest that IL-2 failure drives a large component of cytotoxic functional decline rather than solely checkpoint receptor-ligand interactions that have been the focus of current anti-exhaustion therapies. Clinical evaluations confirm elevated YY1 and Ezh2 in melanoma tumor-infiltrating lymphocytes and in PD1+ T cells in patients with HIV. Exhaustion is revealed to be an active process as the culmination of repetitive two-signal stimulation in a feedback loop via CD3/CD28→p38MAPK/JNK→YY1→ exhaustion. Transcription factor YY1 is shown to serve as master regulator of T cell exhaustion YY1 recruits Ezh2 histone methyltransferase to co-repress IL-2 cytokine production Persistent signal 1+2 stimulation via p38MAPK/JNK pathway promotes YY1 transcription In vivo melanoma and HIV exhausted PD1+ T cells are confirmed for elevated YY1 and Ezh2 Cancer Systems Biology; Immune Response; Immune System Disorder
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影响因子：
7.3
作者：
Atchison ML
通讯作者：
Atchison ML
DOI：
10.1158/1078-0432.ccr-07-4910
发表时间：
2008-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Emtage PC;Lo AS;Gomes EM;Liu DL;Gonzalo-Daganzo RM;Junghans RP
通讯作者：
Junghans RP
DOI：
10.1073/pnas.1214682110
发表时间：
2013-01-02
影响因子：
11.1
作者：
Hwang, Soo Seok;Kim, Young Uk;Lee, Gap Ryol
通讯作者：
Lee, Gap Ryol
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
64.5
作者：
FRESHNEY, NW;RAWLINSON, L;SAKLATVALA, J
通讯作者：
SAKLATVALA, J