Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 47, Pages 12542-12547Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715363114
Keywords
Lkb1; Treg; Foxp3; cellular metabolism; autoimmune disease
Categories
Funding
- NIH [105278]
- Ipsen/Biomeasure
- National Institute of Environmental Health Sciences [P42ES010337]
- T32 Institutional Research Training Grant [5T32CA009370]
- National Institutes of Health (NIH) [DK057978, HL105278, HL088093, CA014195]
- Leona M. and Harry B. Helmsley Charitable Trust [2017-PG-MED001]
- Fondation Leducq
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The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance.
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