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Open AccessArticle

HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells

by Lin Dong 1,†, Ying He 1,†, Shuping Zhou 2,†, Yejin Cao 1, Yan Li 1, Yujing Bi 3,* and Guangwei Liu 1,*
1
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
2
Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan 250062, China
3
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(11), 1450; https://doi.org/10.3390/cells8111450
Received: 14 October 2019 / Revised: 14 November 2019 / Accepted: 15 November 2019 / Published: 17 November 2019
(This article belongs to the Section Cellular Immunology)
Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1α-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response. View Full-Text
Keywords: follicular helper T cell; T cell differentiation; HIF1α; glycolysis; oxidative phosphorylation; virus infection; infectious inflammation; GC responses; B cell immunity follicular helper T cell; T cell differentiation; HIF1α; glycolysis; oxidative phosphorylation; virus infection; infectious inflammation; GC responses; B cell immunity
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Dong, L.; He, Y.; Zhou, S.; Cao, Y.; Li, Y.; Bi, Y.; Liu, G. HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells. Cells 2019, 8, 1450.

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