In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells.
In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells.
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体内CRISPR筛选揭示了HIF-1α-mTOR网络调节T滤泡辅助细胞相对于Th 1细胞。
DOI：
10.1038/s41467-022-28378-6
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发表时间：
2022-02-10
影响因子：
16.6
通讯作者：
Schwartzberg PL
中科院分区：
文献类型：
--
作者：
Huang B;Phelan JD;Preite S;Gomez-Rodriguez J;Johansen KH;Shibata H;Shaffer AL 3rd;Xu Q;Jeffrey B;Kirby M;Anderson S;Yang Y;Gossa S;McGavern DB;Staudt LM;Schwartzberg PL
滤泡辅助性T细胞（Tfh）提供启动和维持生发中心（GC）反应的信号，对于产生稳健、长寿的抗体反应至关重要，但GC微环境如何影响Tfh细胞尚不清楚。在这里，我们开发了一种体内T细胞内在CRISPR敲除筛选，以评估急性病毒感染模型中的Tfh和Th 1细胞，以确定Tfh细胞在其生理环境中的调节因子。通过筛选药物靶点，结合遗传学、转录组学和细胞学分析，我们确定了HIF-1α在抑制mTORC 1介导的和Myc相关通路中的功能，并提供了VHL介导的HIF-1α降解是Tfh发育所必需的证据;扩大的体内CRISPR筛选揭示了调节Tfh相对于Th 1细胞的这些途径的多种组分，包括信号分子，细胞周期调节剂，营养转运蛋白、代谢酶和自噬介质。总的来说，我们的数据作为研究Tfh与Th 1决定的资源，并暗示VHL-HIF-1α轴微调Tfh生成。滤泡辅助性T细胞（Tfh）和辅助性T细胞1型（Th 1）细胞都来自幼稚的CD 4 T细胞，但对其分化的详细了解仍然不完整。在这里，作者进行了体内CRISPR筛选以识别基因，重点是可药用靶点，调节Tfh与Th 1，为相关研究提供资源，同时还涉及HIF-1α和VHL。
T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation. T follicular helper (Tfh) and T help type 1 (Th1) cells both arise from naïve CD4 T cells, but detailed knowledge of their differentiation remains incomplete. Here the authors pursue an in vivo CRISPR screen to identify genes, focusing on druggable targets, regulating Tfh versus Th1 to provide a resource for related studies, while also implicating HIF-1α and VHL in this regulation.
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影响因子：
16.6
作者：
Choi SC;Titov AA;Abboud G;Seay HR;Brusko TM;Roopenian DC;Salek-Ardakani S;Morel L
通讯作者：
Morel L
影响因子：
32.4
作者：
Choi YS;Kageyama R;Eto D;Escobar TC;Johnston RJ;Monticelli L;Lao C;Crotty S
通讯作者：
Crotty S
影响因子：
64.8
作者：
Cho, Sung Hoon;Raybuck, Ariel L.;Stengel, Kristy;Wei, Mei;Beck, Thomas C.;Volanakis, Emmanuel;Thomas, James W.;Hiebert, Scott;Haase, Volker H.;Boothby, Mark R.
通讯作者：
Boothby, Mark R.
影响因子：
9.1
作者：
Bousfiha A;Jeddane L;Picard C;Ailal F;Bobby Gaspar H;Al-Herz W;Chatila T;Crow YJ;Cunningham-Rundles C;Etzioni A;Franco JL;Holland SM;Klein C;Morio T;Ochs HD;Oksenhendler E;Puck J;Tang MLK;Tangye SG;Torgerson TR;Casanova JL;Sullivan KE
通讯作者：
Sullivan KE
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.