Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine

Fu, Guotong; Guy, Clifford S.; Chapman, Nicole M.; Palacios, Gustavo; Wei, Jun; Zhou, Peipei; Long, Ling; Wang, Yongdong; Qian, Chenxi; Dhungana, Yogesh; Huang, Hongling; Kc, Anil; Shi, Hao; Rankin, Sherri L.; Brown, Scott A.; Johnson, Amanda; Wakefield, Randall; Robinson, Camenzind G.; Liu, Xueyan; Sheyn, Anthony; Yu, Jiyang; Jackowski, Suzanne; Chi, Hongbo

doi:10.1038/s41586-021-03692-z

Cited by 91 publications

(53 citation statements)

References 48 publications

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“…Although the requirement for cell expansion in response to infection limits the numbers of sgRNAs we could evaluate in vivo, our use of curated targeted libraries provides a powerful tool to interrogate specific pathways or classes of proteins. Our work complements other in vivo studies [77][78][79][80][81][82][83] by taking advantage of a rapid screen for T cell differentiation in a physiological setting that does not require a selective advantage 77 . Furthermore, our highly efficient vector system allowed the targeting of multiple individual genes, facilitating genetic complementation and network analyses.…”

Section: Discussionmentioning

confidence: 81%

In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 81%

In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells

et al. 2022

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“…Pofut1 deletion reduced the TE’ frequency but improved the accumulation of Cxcr3 hi CD127 lo effector T cells in a poised state (T INT ) that have cytotoxic features. Application of CRISPR-Cas9 screening followed by in vivo validation revealed de novo synthesis of phosphatidylethanolamine as a metabolic and posttranscriptional regulator of CXCR5 protein stability and membrane localization in T follicular helper cells [ 52 ]. In another study, using CRISPR-Cas9-based screening of metabolism-associated factors, Wei et al identified zinc finger CCCH-type containing 12 A or Zc3h12a (also known as Regnase-1) as a major negative regulator of antitumor response [ 53 ].…”

Section: Experimental Approaches To Interrogate Immunometabolismmentioning

confidence: 99%

Systems-based approaches to study immunometabolism

et al. 2022

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Technical advances at the interface of biology and computation, such as single-cell RNA-sequencing (scRNA-seq), reveal new layers of complexity in cellular systems. An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells. The diverse spectra of immune cell phenotypes, sparsity of immune cell numbers in vivo, limitations in the number of metabolites identified, dynamic nature of cellular metabolism and metabolic fluxes, tissue specificity, and high dependence on the local milieu make investigations in immunometabolism challenging, especially at the single-cell level. In this review, we define the systemic nature of immunometabolism, summarize cell- and system-based approaches, and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells. We close the review by discussing the applications and shortcomings of, and challenges faced by metabolic modeling techniques. With systems-oriented studies of metabolism expected to become a mainstay of immunological research, an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.

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“…This metabolic feature associates with Twist-1 expression that promotes FA oxidation and protects the lymphocytes against oxidative stress [93]. Interestingly, follicular helper T cells, which are essential for the activation of B lymphocytes and humoral immunity, require the activation of phosphoethanolamine synthesis as a key step for differentiation [94].…”

Section: Cd4 T Lymphocytes and Fatty Acid Metabolismmentioning

confidence: 99%

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

Neto

Calder

Curi

et al. 2021

IJMS

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Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports optimal immune function, including the inflammatory response. In this review, we will focus on metabolism in macrophages and lymphocytes and discuss the role of fatty acids in governing the phenotype, activation, and functional status of these important cells. We summarize the current understanding of the pathways of fatty acid metabolism and related mechanisms of action and also explore possible new perspectives in this exciting area of research.

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Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine

Cited by 91 publications

References 48 publications

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

Systems-based approaches to study immunometabolism

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

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