Journal article
Metabolic modeling of single Th17 cells reveals regulators of autoimmunity
Cell, Vol.184(16), pp.4168-4185
05/Aug/2021
PMID: 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.
Details
- Title
- Metabolic modeling of single Th17 cells reveals regulators of autoimmunity
- Creators
- Allon Wagner - University of California, BerkeleyChao Wang - Broad InstituteJohannes Fessler - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USADavid DeTomaso - University of California, BerkeleyJulian Avila-Pacheco - Broad InstituteJames Kaminski - University of California, BerkeleySarah Zaghouani - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USAElena Christian - Broad InstitutePratiksha Thakore - Broad InstituteBrandon Schellhaass - University of California, BerkeleyElliot Akama-Garren - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USAKerry Pierce - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USAVasundhara Singh - Broad InstituteNoga Ron-Harel - Technion – Israel Institute of TechnologyVivian Paraskevi Douglas - Harvard Medical SchoolLloyd Bod - Brigham and Women's HospitalAlexandra Schnell - Brigham and Women's HospitalDaniel Puleston - Max Planck Institute of Immunobiology and EpigeneticsRaymond A. Sobel - Palo Alto Veteran’s Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USAMarcia Haigis - Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USAErika L. Pearce - Max Planck Institute of Immunobiology and EpigeneticsManoocher Soleimani - University of New MexicoClary Clish - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USAAviv Regev - Massachusetts Institute of TechnologyVijay K. Kuchroo (Corresponding Author) - Brigham and Women's HospitalNir Yosef (Corresponding Author) - University of California, Berkeley
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.184(16), pp.4168-4185; 05/Aug/2021
- Number of pages
- 18
- Publisher
- Elsevier Inc
- Language
- English
- DOI
- https://doi.org/10.1016/j.cell.2021.05.045
- PMID
- 34216539
- Grant note
- We thank Eytan Ruppin and Michael B. Cole for fruitful discussions and Christina Usher for artwork. N.Y. and A.W. were supported by the Chan Zuckerberg Biohub and by the National Institute of Mental Health (NIMH) (NIH5U19MH114821). C.W. is a Medicine by Design Investigator supported by Canada First Research Excellence Fund. This work was supported by grants from the NIH (RO1NS30843, R01AI144166, R01NS045937, P01AI073748, P01AI039671, and P01AI056299 to V.K.K.) and by a Career Transitional Fellowship and faculty phase grant (TA-1605-08590 to C.W.) from the National Multiple Sclerosis Society. J.F. was supported by a Max Kade fellowship awarded by the Austrian Academy of Science (ÖAW). Author contributions - A.W., C.W., A.R., V.K.K., and N.Y. conceived and designed the study. A.W., D.D.T., and N.Y. designed the algorithm and performed computational analyses, B.S. aided in software development. C.W. conceived, designed, performed, and analyzed most experiments, with significant contributions by V.K.K., J.A.-P., K.P., and C.C. in LC/MS metabolomics and J.F. and S.Z. in inhibitor experiments. J.K. analyzed ATAC-seq datasets. E.C. generated most sequencing libraries. P.T. and V.S. provided help with ATAC-seq experiments. P.T. and A.S. optimized ATAC-seq protocol with input from A.R. R.S. performed histological analysis of EAE experiments. E.A.-G., L.B., and V.P.D. provided further experimental and analytical assistance. N.R.-H. and M.H. provided Seahorse assay support. D.P., E.P., and M.S. provided critical materials. V.K.K., N.Y., and C.W. supervised the study. A.W., C.W., V.K.K., and N.Y. wrote the manuscript with contributions from all authors. All authors read and approved the final manuscript.
- Record Identifier
- 993421083603596
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