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T follicular helper (T.sub.FH) cells are crucial for B cell-mediated humoral immunity.sup.1. Although transcription factors such as BCL6 drive the differentiation of T.sub.FH cells.sup.2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce T.sub.FH cell programming. Here we show that the cytidine diphosphate (CDP)-ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of T.sub.FH cells and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI--enzymes in the CDP-ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)--as selective post-transcriptional regulators of T.sub.FH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. T.sub.FH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP-ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP-choline pathway), in activated T cells impairs the differentiation of T.sub.FH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for T.sub.FH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs. Enzymes in the cytidine diphosphate-ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (T.sub.FH) cells, by regulating the chemokine receptor CXCR5., Author(s): Guotong Fu [sup.1] , Clifford S. Guy [sup.1] , Nicole M. Chapman [sup.1] , Gustavo Palacios [sup.1] , Jun Wei [sup.1] , Peipei Zhou [sup.1] , Lingyun Long [sup.1] [...]

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.

Regulatory T cells (T.sub.reg cells) are essential for immune tolerance.sup.1, but also drive immunosuppression in the tumour microenvironment.sup.2. Therapeutic targeting of T.sub.reg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in T.sub.reg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral T.sub.reg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)--a factor required for SREBP activity--in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-[gamma] and impaired function of intratumoral T.sub.reg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of T.sub.reg cells, and loss of FASN from T.sub.reg cells inhibits tumour growth. Second, T.sub.reg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral T.sub.reg cells. Our findings show that metabolic reprogramming enforces the functional specialization of T.sub.reg cells in tumours, pointing to new ways of targeting these cells for cancer therapy. Identification of a metabolic checkpoint involving lipid signalling that is specific to regulatory T cells (T.sub.reg cells) in the tumour microenvironment raises the possibility of targeting this checkpoint for treatment of cancer., Author(s): Seon Ah Lim [sup.1] , Jun Wei [sup.1] , Thanh-Long M. Nguyen [sup.1] , Hao Shi [sup.1] , Wei Su [sup.1] , Gustavo Palacios [sup.1] , Yogesh Dhungana [sup.1] [...]

Author(s): Nathan D. Grubaugh [1]; Jason T. Ladner [2]; Moritz U. G. Kraemer [3, 4, 5]; Gytis Dudas [6]; Amanda L. Tan [7]; Karthik Gangavarapu [1]; Michael R. Wiley [2, [...]

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.Enzymes in the cytidine diphosphate–ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (TFH) cells, by regulating the chemokine receptor CXCR5. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)—a factor required for SREBP activity—in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-γ and impaired function of intratumoral Treg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.Identification of a metabolic checkpoint involving lipid signalling that is specific to regulatory T cells (Treg cells) in the tumour microenvironment raises the possibility of targeting this checkpoint for treatment of cancer. [ABSTRACT FROM AUTHOR]