Metabolic modeling of single Th17 cells reveals regulators of autoimmunity

Allon Wagner; Chao Wang; Johannes Fessler; David DeTomaso; Julian Avila-Pacheco; James Kaminski; Sarah Zaghouani; Elena Christian; Pratiksha Thakore; Brandon Schellhaass; Elliot Akama-Garren; Kerry Pierce; Vasundhara Singh; Noga Ron-Harel; Vivian Paraskevi Douglas; Lloyd Bod; Alexandra Schnell; Daniel Puleston; Raymond A Sobel; Marcia Haigis; Erika L Pearce; Manoocher Soleimani; Clary Clish; Aviv Regev; Vijay K Kuchroo; Nir Yosef

doi:10.1016/j.cell.2021.05.045

Metabolic modeling of single Th17 cells reveals regulators of autoimmunity

Cell. 2021 Aug 5;184(16):4168-4185.e21. doi: 10.1016/j.cell.2021.05.045. Epub 2021 Jul 2.

Authors

Allon Wagner¹, Chao Wang², Johannes Fessler³, David DeTomaso⁴, Julian Avila-Pacheco⁵, James Kaminski⁴, Sarah Zaghouani³, Elena Christian⁵, Pratiksha Thakore⁵, Brandon Schellhaass⁶, Elliot Akama-Garren³, Kerry Pierce⁵, Vasundhara Singh⁵, Noga Ron-Harel⁷, Vivian Paraskevi Douglas⁸, Lloyd Bod³, Alexandra Schnell³, Daniel Puleston⁹, Raymond A Sobel¹⁰, Marcia Haigis¹¹, Erika L Pearce⁹, Manoocher Soleimani¹², Clary Clish⁵, Aviv Regev¹³, Vijay K Kuchroo¹⁴, Nir Yosef¹⁵

Affiliations

¹ 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.
² 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, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: chao.wang@sri.utoronto.ca.
³ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
⁷ Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
⁸ Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
⁹ Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
¹⁰ Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87121, USA.
¹³ 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.
¹⁴ 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.
¹⁵ 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, and Harvard, Cambridge, MA 02139, USA. Electronic address: niryosef@berkeley.edu.

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.

Keywords: DFMO; T helper 17 cell; experimental autoimmune encephalomyelitis; immunometabolism; in silico metabolic modeling; multiple sclerosis; polyamines; putrescine; single cell transcriptomics; spermidine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetyltransferases / metabolism
Adenosine Triphosphate / metabolism
Aerobiosis / drug effects
Algorithms
Animals
Autoimmunity / drug effects
Autoimmunity / immunology*
Chromatin / metabolism
Citric Acid Cycle / drug effects
Cytokines / metabolism
Eflornithine / pharmacology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / pathology
Epigenome
Fatty Acids / metabolism
Glycolysis / drug effects
Jumonji Domain-Containing Histone Demethylases / metabolism
Mice
Mice, Inbred C57BL
Mitochondrial Membrane Transport Proteins / metabolism
Models, Biological*
Oxidation-Reduction / drug effects
Putrescine / metabolism
Single-Cell Analysis
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
Th17 Cells / drug effects
Th17 Cells / immunology*
Transcriptome / genetics

Substances

Chromatin
Cytokines
Fatty Acids
Mitochondrial Membrane Transport Proteins
Adenosine Triphosphate
Jumonji Domain-Containing Histone Demethylases
Kdm6b protein, mouse
Acetyltransferases
diamine N-acetyltransferase
Putrescine
Eflornithine

Abstract

Publication types

MeSH terms

Substances

Grants and funding