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

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-intrinsi...

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Autores principales: Huang, Bonnie, Phelan, James D., Preite, Silvia, Gomez-Rodriguez, Julio, Johansen, Kristoffer H., Shibata, Hirofumi, Shaffer, Arthur L., Xu, Qin, Jeffrey, Brendan, Kirby, Martha, Anderson, Stacie, Yang, Yandan, Gossa, Selamawit, McGavern, Dorian B., Staudt, Louis M., Schwartzberg, Pamela L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831505/
https://www.ncbi.nlm.nih.gov/pubmed/35145086
http://dx.doi.org/10.1038/s41467-022-28378-6
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author Huang, Bonnie
Phelan, James D.
Preite, Silvia
Gomez-Rodriguez, Julio
Johansen, Kristoffer H.
Shibata, Hirofumi
Shaffer, Arthur L.
Xu, Qin
Jeffrey, Brendan
Kirby, Martha
Anderson, Stacie
Yang, Yandan
Gossa, Selamawit
McGavern, Dorian B.
Staudt, Louis M.
Schwartzberg, Pamela L.
author_facet Huang, Bonnie
Phelan, James D.
Preite, Silvia
Gomez-Rodriguez, Julio
Johansen, Kristoffer H.
Shibata, Hirofumi
Shaffer, Arthur L.
Xu, Qin
Jeffrey, Brendan
Kirby, Martha
Anderson, Stacie
Yang, Yandan
Gossa, Selamawit
McGavern, Dorian B.
Staudt, Louis M.
Schwartzberg, Pamela L.
author_sort Huang, Bonnie
collection PubMed
description 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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spelling pubmed-88315052022-03-04 In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells Huang, Bonnie Phelan, James D. Preite, Silvia Gomez-Rodriguez, Julio Johansen, Kristoffer H. Shibata, Hirofumi Shaffer, Arthur L. Xu, Qin Jeffrey, Brendan Kirby, Martha Anderson, Stacie Yang, Yandan Gossa, Selamawit McGavern, Dorian B. Staudt, Louis M. Schwartzberg, Pamela L. Nat Commun Article 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. Nature Publishing Group UK 2022-02-10 /pmc/articles/PMC8831505/ /pubmed/35145086 http://dx.doi.org/10.1038/s41467-022-28378-6 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Huang, Bonnie
Phelan, James D.
Preite, Silvia
Gomez-Rodriguez, Julio
Johansen, Kristoffer H.
Shibata, Hirofumi
Shaffer, Arthur L.
Xu, Qin
Jeffrey, Brendan
Kirby, Martha
Anderson, Stacie
Yang, Yandan
Gossa, Selamawit
McGavern, Dorian B.
Staudt, Louis M.
Schwartzberg, Pamela L.
In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title_full In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title_fullStr In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title_full_unstemmed In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title_short In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
title_sort in vivo crispr screens reveal a hif-1α-mtor-network regulates t follicular helper versus th1 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831505/
https://www.ncbi.nlm.nih.gov/pubmed/35145086
http://dx.doi.org/10.1038/s41467-022-28378-6
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