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

doi:10.1016/j.cmet.2019.11.021

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 journal › Article › peer-review

202 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 language	English (US)
Pages (from-to)	422-437.e5
Journal	Cell Metabolism
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2019.11.021
State	Published - Feb 4 2020

Bibliographical note

Funding Information:
E.L.P. is a SAB member of Immunomet, and E.L.P. and E.J.P. are founders of Rheos Medicines. B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc., Five Prime Therapeutics Inc., Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc., Abbvie Inc., BlueRock Therapeutics Leukemia and Lymphoma Society, Childrens’ Cancer Research Fund, and KidsFirst Fund and is a co-founder of Tmunity.

Funding Information:
We thank G. Hotamisligil for sharing the Fabp4/5 dKO mice and Johan Friden for assistance with the graphical abstract. This work was supported by grants from the National Institutes of Health R01 HL11879 and R37 AI34495 (B.R.B.), P01 CA065493 (B.R.B.; K.L.H.), R01 AI110481 (E.J.P.), R01 CA181125 (E.L.P.), and the Max Planck Society . F.B. and M.C. are supported by a Humboldt Fellowship from the Humboldt Foundation . D.J.P. is supported by a Sir Henry Wellcome Fellowship from the Wellcome Trust .

Publisher Copyright:
© 2019 The Authors

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Field, C. S., Baixauli, F., Kyle, R. L., Puleston, D. J., Cameron, A. M., Sanin, D. E., Hippen, K. L., Loschi, M., Thangavelu, G., Corrado, M., Edwards-Hicks, J., Grzes, K. M., Pearce, E. J., Blazar, B. R., & Pearce, E. L. (2020). Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function. Cell Metabolism, 31(2), 422-437.e5. https://doi.org/10.1016/j.cmet.2019.11.021

Field, CS, Baixauli, F, Kyle, RL, Puleston, DJ, Cameron, AM, Sanin, DE, Hippen, KL, Loschi, M, Thangavelu, G, Corrado, M, Edwards-Hicks, J, Grzes, KM, Pearce, EJ, Blazar, BR & Pearce, EL 2020, 'Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function', Cell Metabolism, vol. 31, no. 2, pp. 422-437.e5. https://doi.org/10.1016/j.cmet.2019.11.021

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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.",

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AU - Sanin, David E.

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AU - Loschi, Michael

AU - Thangavelu, Govindarajan

AU - Corrado, Mauro

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AU - Grzes, Katarzyna M.

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AB - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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