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Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.
Wagner, Allon; Wang, Chao; Fessler, Johannes; DeTomaso, David; Avila-Pacheco, Julian; Kaminski, James; Zaghouani, Sarah; Christian, Elena; Thakore, Pratiksha; Schellhaass, Brandon; Akama-Garren, Elliot; Pierce, Kerry; Singh, Vasundhara; Ron-Harel, Noga; Douglas, Vivian Paraskevi; Bod, Lloyd; Schnell, Alexandra; Puleston, Daniel; Sobel, Raymond A; Haigis, Marcia; Pearce, Erika L; Soleimani, Manoocher; Clish, Clary; Regev, Aviv; Kuchroo, Vijay K; Yosef, Nir.
Afiliação
  • Wagner A; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Wang C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology
  • Fessler J; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • DeTomaso D; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Avila-Pacheco J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kaminski J; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Zaghouani S; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Christian E; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Thakore P; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Schellhaass B; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Akama-Garren E; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Pierce K; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Singh V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Ron-Harel N; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
  • Douglas VP; Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
  • Bod L; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Schnell A; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Puleston D; Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  • Sobel RA; Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Haigis M; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Pearce EL; Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  • Soleimani M; Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87121, USA.
  • Clish C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Regev A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
  • Kuchroo VK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu.
  • Yosef N; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA; Ragon Institute of MGH, MIT, an
Cell ; 184(16): 4168-4185.e21, 2021 08 05.
Article em En | MEDLINE | ID: mdl-34216539
ABSTRACT
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoimunidade / Células Th17 / Modelos Biológicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoimunidade / Células Th17 / Modelos Biológicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos