2. Academic Validation
  3. Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function

Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function

  • Cell Metab. 2020 Feb 4;31(2):422-437.e5. doi: 10.1016/j.cmet.2019.11.021.
Cameron S Field 1,  Francesc Baixauli 1,  Ryan L Kyle 1,  Daniel J Puleston 2,  Alanna M Cameron 1,  David E Sanin 1,  Keli L Hippen 3,  Michael Loschi 3,  Govindarajan Thangavelu 3,  Mauro Corrado 1,  Joy Edwards-Hicks 1,  Katarzyna M Grzes 1,  Edward J Pearce 4,  Bruce R Blazar 3,  Erika L Pearce 5
Affiliations

Affiliations

  • 1 Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  • 2 Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany; The Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK.
  • 3 Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 4 Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
  • 5 Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: pearce@ie-freiburg.mpg.de.
PMID: 31883840 DOI: 10.1016/j.cmet.2019.11.021
Abstract

Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.

Keywords

FABP5; IL-10; Treg; cGAS-STING; immunometabolism; lipids; mtDNA; suppression; tumor; type I IFN.

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