Brd4 Regulates the Homeostasis of CD8(+) T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation.
Brd4 Regulates the Homeostasis of CD8(+) T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation.
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DOI：
10.3389/fimmu.2021.728082
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Peng Z;Zhang Y;Ma X;Zhou M;Wu S;Song Z;Yuan Y;Chen Y;Li Y;Wang G;Huang F;Qiao Y;Xia B;Liu W;Liu J;Zhang X;He X;Pan T;Xu H;Zhang H
CD8+ T细胞是适应性免疫的主要组成部分，并赋予强大的保护性细胞免疫，这需要足够的T细胞数量、靶向迁移和有效的T细胞增殖。CD8+ t细胞稳态改变和增殖受损导致感染或肿瘤发生的功能失调免疫反应。然而，控制CD8+ t细胞稳态和免疫的内在因素在很大程度上仍然是难以捉摸的。在这里，我们证明了Brd4在CD8+ T细胞稳态和免疫反应中的突出作用。通过上调Myc和GLUT1的表达，Brd4促进线粒体中的葡萄糖摄取和能量产生，随后支持naïve CD8+ t细胞的存活。此外，Brd4通过维持归巢受体（CD62L和LFA-1）的表达，部分促进naïve CD8+ T细胞的运输。此外，Brd4是CD8+ T细胞对抗原刺激的反应所必需的，因为Brd4缺乏会通过减少糖酵解导致克隆扩增和终末分化的严重缺陷。重要的是，由于JQ1是一种泛brd抑制剂，严重抑制CD8+ t细胞免疫应答，因此将其用作人类免疫缺陷病毒I型（HIV-1）的抗肿瘤剂或逆转潜伏剂应更加谨慎。总的来说，我们的研究确定了Brd4在CD8+ T细胞介导的免疫监视的代谢调节中的先前意想不到的作用，并且还提供了一个潜在的免疫调节靶点。
CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.
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影响因子：
8.8
作者：
Gegonne A;Chen QR;Dey A;Etzensperger R;Tai X;Singer A;Meerzaman D;Ozato K;Singer DS
通讯作者：
Singer DS
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.5
作者：
Kannan-Sundhari A;Abad C;Maloof ME;Ayad NG;Young JI;Liu XZ;Walz K
通讯作者：
Walz K
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
11.4
作者：
Dey, Anup;Yang, Wenjing;Ozato, Keiko
通讯作者：
Ozato, Keiko