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

被引：294

作者：

Field, Cameron S. ^{[1
]}

Baixauli, Francesc ^{[1
]}

Kyle, Ryan L. ^{[1
,5
]}

Puleston, Daniel J. ^{[1
,3
]}

Cameron, Alanna M. ^{[1
,6
]}

Sanin, David E. ^{[1
]}

Hippen, Keli L. ^{[2
]}

Loschi, Michael ^{[2
]}

Thangavelu, Govindarajan ^{[2
]}

Corrado, Mauro ^{[1
]}

Edwards-Hicks, Joy ^{[1
]}

Grzes, Katarzyna M. ^{[1
]}

Pearce, Edward J. ^{[1
,4
]}

Blazar, Bruce R. ^{[2
]}

Pearce, Erika L. ^{[1
]}

机构：

[1] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany

[2] Univ Minnesota, Mason Canc Ctr, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN USA

[3] Univ Oxford, Kennedy Inst Rheumatol, Oxford OX3 7FY, England

[4] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany

[5] GSK, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[6] Sitryx Therapeut, Magdalen Ctr, Oxford Sci Pk, Oxford OX4 4GA, England

来源：

CELL METABOLISM | 2020年 / 31卷 / 02期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

ACID-BINDING PROTEIN; T-CELLS; RETINOIC ACID; OXIDATIVE-PHOSPHORYLATION; CRYSTAL-STRUCTURE; IL-10; PRODUCTION; I INTERFERONS; FATTY-ACIDS; CANCER; STRESS;

D O I：

10.1016/j.cmet.2019.11.021

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：422 / +

页数：21

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