Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis
Sander de Kivit,
Mark Mensink,
Sarantos Kostidis,
Rico J.E. Derks,
Esther A. Zaal,
Marieke Heijink,
Lotte J. Verleng,
Evert de Vries,
Ellen Schrama,
Niek Blomberg,
Celia R. Berkers,
Martin Giera,
Jannie Borst
Affiliations
Sander de Kivit
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Corresponding author
Mark Mensink
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Sarantos Kostidis
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Rico J.E. Derks
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Esther A. Zaal
Division of Cell Biology, Metabolism, and Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands
Marieke Heijink
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Lotte J. Verleng
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Evert de Vries
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Ellen Schrama
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Niek Blomberg
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Celia R. Berkers
Division of Cell Biology, Metabolism, and Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands
Martin Giera
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Jannie Borst
Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Corresponding author
Summary: Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.
