The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity
Chao Wang,
Allon Wagner,
Johannes Fessler,
David DeTomaso,
Sarah Zaghouani,
Yulin Zhou,
Kerry Pierce,
Raymond A. Sobel,
Clary Clish,
Nir Yosef,
Vijay K. Kuchroo
Affiliations
Chao Wang
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Allon Wagner
Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Johannes Fessler
Division of Immunology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
David DeTomaso
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Sarah Zaghouani
The Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Mass General Hospital and Harvard Medical School, Boston, MA 02115, USA
Yulin Zhou
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Kerry Pierce
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Raymond A. Sobel
Palo Alto Veteran’s Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Clary Clish
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Nir Yosef
Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Corresponding author
Vijay K. Kuchroo
The Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Mass General Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Summary: Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.
