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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number114681
JournalCell Reports
Volume43
Issue number9
DOIs
Publication statusPublished - 24 Sept 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords

  • (regulatory) T cell
  • costimulation
  • CP: Immunology
  • CP: Metabolism
  • fatty acids
  • glycolysis
  • immune suppression
  • isotopologue tracing
  • lactate
  • lipidomics
  • mass spectrometry
  • metabolism

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