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

Field, Cameron; Baixauli Celda, Francesc; Puleston, Daniel; Kyle, Ryan; Alana, Cameron; Sanin, Pena David Estaban; Hippen, Keli L.; Loschi, Michael; Thangavelu, Govindarajan; Corrado, Mauro; Edwards-Hicks, Joy; Grzes, Katarzyna; Pearce, Edward J.; Blazar, Bruce R.; Pearce, Erika L.

doi:10.1016/j.cmet.2019.11.021

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

MPS-Authors

Field, Cameron
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204369

Baixauli Celda, Francesc
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204373

Puleston, Daniel
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kyle, Ryan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201436

Alana, Cameron
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201442

Sanin, Pena David Estaban
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201354

Corrado, Mauro
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Edwards-Hicks, Joy
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204377

Grzes, Katarzyna
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201435

Pearce, Edward J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce, Erika L.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.sciencedirect.com/science/article/pii/S1550413119306655?via%3Dihub
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Citation

Field, C., Baixauli Celda, F., Puleston, D., Kyle, R., Alana, C., Sanin, P. D. E., et al. (2020). Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function. Cell Metabolism, 31, 422-437. doi:10.1016/j.cmet.2019.11.021.

Cite as: https://hdl.handle.net/21.11116/0000-0006-3B94-1

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.