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.


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


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