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

Cameron S. Field, Francesc Baixauli, Ryan L. Kyle, Daniel J. Puleston, Alanna M. Cameron, David E. Sanin, Keli L. Hippen, Michael Loschi, Govindarajan Thangavelu, Mauro Corrado, Joy Edwards-Hicks, Katarzyna M. Grzes, Edward J. Pearce, Bruce R. Blazar, Erika L. Pearce

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

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.

Original languageEnglish
Pages (from-to)422-437.e5
JournalCell Metabolism
Volume31
Issue number2
DOIs
StatePublished - 4 Feb 2020
Externally publishedYes

Keywords

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

Fingerprint

Dive into the research topics of 'Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function'. Together they form a unique fingerprint.

Cite this